G Protein Coupled Receptors

today we are going to talk about g protein coupled receptors g protein coupled receptors which are also called seven pass receptors and which are also called serpentine receptors because they seven time passes the membrane and look like a sneaky shape like a snake right so wherever in the literature medical literature you study g protein coupled receptor or seven path receptor or serpentine receptor they are one and the same thing right but before really i in this lecture what we will be doing first of all we will discuss about the structure of the receptor how this receptor is structured what are important domains like right and then we'll talk about activation and function of the receptor after that will go how these receptors are activated and how these are inactivated right and what is the difference between inactivation of receptor and desensitization and how receptors undergo desensitization and how receptors can be re-sensitized and then we will talk about down regulation of seven path receptors and up regulation of seven pass receptors because why i included especially this component because many students get confused about inactivation of receptors or desensitization of receptors or down regulation of receptor but today we will try our best to make it crystal clear differences among these conditions right so before really i discuss g protein coupled receptor let me discuss about basic concept that what is receptor right what is receptor receptor is actually uh we are uh there are two types of receptors they are sensory receptors sensory receptors which are related with especially with the neurological system right there are sensory receptors like uh taste buds like rods and cones right like pacinian corpuscles these are sensory receptors we will not talk about these receptors today we will not talk about sensory receptors today our discussion is about those receptors those macromolecules right which are specially related with physiology biochemistry and pharmacology right so we will limit ourselves to those receptors which are specially involved in biological system related with physiology biochemistry and especially pharmacology right now what is receptor receptor is any macromolecule what it is it is any macromolecule macro molecule or complex of macromolecules complex of macro molecules right in old time we used to say that such receptors are generally protein receptors yes this is right generally these receptors are proteins or peptides but some of the receptors are not proteins or peptides like dna dna is a macromolecule of course it is not protein and some of the drugs directly act on the dna for example alkylating agents right anti-cancer drug some of the anti-cancer drugs directly act on the dna so for those drugs dna itself is a receptor right that is why now we have changed the definition we don't say that receptors are proteins we say they are macromolecules which may be proteins which might be dna or that might be rna or any other big molecule or complexes of big molecules is that right so receptors are macromolecules or complexes of macromolecules which have special two functions they should have at least two two functions or rather i should say two functional domains they should have two functional domains right two functional domain mean there should be one domain for example if this is a receptor let's suppose this is a receptor right and okay now if this is a receptor one one side of the receptor one domain of the receptor should be such that where a specific molecule can bind and that molecule which can bind here let's suppose this is the molecule which can bind here such molecule would bind with a special domain specific domain of a receptor such molecule is called ligand binding domain what is this this is ligand binding domain how we define ligand ligand is a substance which binds with the receptor and brings the conformational or functional change in the structural and functional change in the receptor to produce some biological response what is likened ligand is the substance which bind with the receptor where it binds with the receptor at the ligand binding domain at the ligand binding domain right and once it bind here it is just like this you irritate my pull my ear and i will you might kick you if you pull my ear so your hand is the ligand my ear is the lag and binding domain and the kick i do or response i do that is biological response is that right okay for this simple thing we can save a ligand bind over here right whenever it brings its tongue and start testing the things around so it is other functional domain first domain was ligand binding domain right second domain is effector domain what is that okay i will make it like again this is okay specifically what is this ligand binding domain right where you can bind some ligand now this ligand may be a hormone maybe a neurotransmitter may be a drug right yes so many so hormones or neurotransmitter or drugs they usually go and bind with the receptor at which domain ligand binding domain and in response to that binding receptor undergo a conformational change under structural and functional change it undergoes a modification and result of that modification will be that when it binds ligand binds and other domain is activated right or inactivated there is some change right this changes this domain is called effector domain factor domain so basically what is receptor receptor is a macromolecule or a complex of macro molecule right which it should have at least two minimum functional domains two functional areas one like and finding domain other effector domain you remain remove it tango in you put it here tongue comes out right so you understand it so is that clear now i will ask a question to you plasma proteins they bind many things plasma proteins like albumin pre albumin and others they bind many hormones and even they bind very many many drugs are plasma proteins receptors yes doctor they are receptors okay do you what do you think they are receptor or not receptor say yes or no no confusion no why they are not receptors they are binding a substance he is saying that plasma protein okay let's suppose here is a plasma protein plasma protein may bind many things but it does not under it does have binding domain but does not have a factor domain plasma proteins do bind many substances but plasma proteins once they bind a substance usually they don't undergo any conformational change and they don't have any effectors a factor domain and usually when substances bind with the plasma proteins they do not produce any special or specific biological response so it is just like that that plasma protein is that you are doing like this but there is no response so just have so everything which in the our body every macro molecule in our body which can bind something right but does not undergo any conformational change and then does not produce any effector biological response that thing cannot be called receptor so plasma proteins are just carrier of hormones or carrier of drugs or we can say they are drug binding they are binding to the hormones and many substances but plasma proteins do not produce once the substance bind with the plasma protein usually plasma protein do not produce any specific response so what i want to hammer in your mind that to be a receptor it should have minimum to minimum two domains two special points at its number one two special qualities number one lag and binding domain and affected domain an effect is produced is that clear right now there are many types of receptors right we are again i'm saying that we are concentrating only on the biochem receptors in biochemistry and pharmacology physiology right now receptors are many types of the receptors i will just talk about their broad categories and then i will go back in detail of g protein coupled receptors yes you have a question uh yes sir actually you say that the receptor binds and then produces a biological response so when this response be limited to the cells only or will it go through the whole system i'm going to tell you actually he asked me a very important question he says that uh when lagging bind with the receptor and i'm saying that there's a biological response is is this biological response only on cell answer is that if it is a cellular receptor if it is on cell membrane or receptor is in the cytosol or receptors in the nucleus then of course there will be change in the cell but if many change many cells undergo changes of course that may produce some biological response which might be cellular or might be systemic right multisystem like adrenaline epinephrine norepinephrine when the epinephrine norepinephrine is injected in the body or dopamine their receptors are present on multi organs and multi systems so they will bring the changes in cells of multiple organs and systems and multisystemic response can come so minimum receptor upon binding with the ligand can produce cellular changes and maximum it can produce multiple multi-systemic biological changes it depends on what is the ligand ligand and what is the distribution of the receptors on the tissues and how they are responding is that right let's come back that these receptors where they are located let me let me make a cell here suppose this is a cell now okay let me make it a bigger cell let's suppose this is cell membrane and here is the nucleus right now what could be the location of the receptors there are some locations almost every student know and there is one location usually student forget right let me tell you the common locations number one is cell membrane some of the receptors are macromolecules usually proteins with some oligosaccharides which are present in the membrane we call them transmembrane receptors or they are integral proteins right then there are some receptors which are in the cytosol right and there are some receptors which have which are present in the nucleus right and there is one more site where their receptor can be these are cellular receptor the cellular receptor might be on the mem inserted on the membrane or appearing on the membrane or they may be in the cytosol or even they might be in the nucleus i will give you examples but tell me one more site any one of these front boys yes anymore site where receptors can be present where receptors can be present that is that is yes yes yes come on that is extracellular site some macromolecules are outside the cells or you can say in extracellular space or in between the cells and some macromolecules are outside the cells and sometimes some substances bind with them and bring the change into that molecule due to effector activity and change biological system you must be thinking what is this you must be thinking but i will not tell you now first i will tell you these common three things and then you have to ask me remind me to tell extracellular receptors right okay let's start with generally general categories main categories of membranous receptors right membranous receptors are number one yes one pass receptors one path receptors are having lag and binding domain outside effector domain inside and one time they pass through the membrane right so this is a peptide let's suppose this is a peptide where it binds the ligand outside the cell right ligand binding domain is extracellular and effector domain is intracellular and one part is passing through the membrane which is called trans membrane part so this strip this receptor has one ligand binding domain one effector domain and in between there is trans membrane component so trans membrane component outside bind with ligand binding domain and inside it is having a factor domain so when ligand bind with extracellular area inter solar start some activity or some biological change or some signaling inside in this way these receptors which we call them transmembrane receptors this whole group is responsible for taking the extra cellular signals right and and under the signals they bring intracellular change they bring biological response inside the cell right they bring alteration in the cell now now this is how many pass one pass receptor so we can say this is one pass receptor classical example of one path receptors are tyrosine kinase receptors insulin receptor yes very good insulin receptor is one pass receptor but let me tell you something interesting when insulin binds with the receptor other receptors also come so two receptors with one insulin two one pass receptors bind with that and that is dimerization that for example this is one pass receptor if insulin bind here it will also bring one more one pass receptor right and two one pass receptors will make a dimer and that dimer will that dimer will bring intracellular changes on the target cells but anyway this is an example of what one pass receptor then there are receptors which are usually of course they consist of peptide chains most of the receptors which are on the membrane they are peptide chains one peptide chain or more than one peptide there are receptors which are not one pass receptor there are more pass receptors like four to five pass receptors there can be four to five pass receptors there may be four or five different peptide units which are going through the membrane or there is one peptide unit but passes through four or five times can you tell me some example of such a receptors yes yes doctor any receptor where peptide unit is the peptide unit is passing through the membrane four or five times right are you going to tell me yes ion channels very good for example ligand binding ion channels let's suppose this is yes this let's suppose this is called energic receptors cholinergic nicotinic receptors acetylcholine will bind here acetal choline will bind here right so this will be ligand binding domain and when it binds here let's suppose it changes the frequency of opening and closing of this receptors so this tunnel through which this tunnel opens and close this canal which opens and close closes this canal is basically yes this canal okay let me tell you exactly this is acting as what a factor component so upon like by ligand binding right upon ligand binding some ion channels undergo conformational change and that alters the flux of movement of the ions right so we call such receptors as yes ligand yes no no these are ion channels but they are operated by ligand binding so ligand gated ion channels or ligand operated ligand operated ion channels such ion channels where function depend on the presence of the ligand and effector unit is basically a canal right a central pore which is opening extracellularly as well as intracellularly and when ligand binds uh basically opening and closing of ah frequency of these canal changes and that brings the biological changes right then there are so this is how many four to four to five pass receptors then with we come to our beloved receptors the most loved one receptors even though they look like snake serpentine receptors they pass through the membrane seven times we call them seven pass receptors and let me draw here uh here is seven pass receptor let's suppose this is one peptide it is just one peptide chain but it passes through the membrane seven times now because this peptide chain is passing through the membrane seven times one two three four five six and seven due to this reason simply they are called seven pass receptors when they were discovered initially that researchers found there is a peptide there are peptides in the membranes which pass through the membrane seven time and they thought when a ligand bind here some changes are in the cell so they said that this is seven pass receptors right in those days they only knew for example if adrenaline binds here right this change in for example cyclic amp levels doctors there was so if catecholamines adrenaline or noradrenaline bind with its with its seven past adrenergic receptor there is intracellular change in cyclic emp levels in in those days many decades back in between what was happening we were not knowing we were just knowing this thing the adrenaline bind with the ligand binding domain and somehow in the cell what happens cyclic amp levels change is that right so then doctors called adrenaline or such molecules first messenger or molecules which were changing in the cell which doctors were able to measure they call this that second messenger that is why neurotransmitters or hormones or drugs they are actually when they go and bind with the ligand binding domain we say first messenger has arrived and ultimate biological change which is coming into cell right in the special molecules we call them second messenger but now over the years we have discovered there are so many things in between for example when ligand binds here right this is ligand binding domain and what is this domain transmembrane domain and what is this domain effector domain right now we have discovered again i will repeat it what is it what is this component lag and binding domain and what is this component effector effector domain this is factor effector domain and this is ligand binding domain and this peptide has one pocket outside where ligand can bind specific ligand and one tail inside right usually this peptide has a minor end outside and three terminal inside is that right you know peptide chain has two ends a minor end and carboxylic carboxylate so what happens these peptide chains when they passes through the membrane seven time they are always keeping amino and outside and they are keeping the carboxylate inside so we say amino terminus is outside extracellular and what is this terminal carboxylic terminal terminal inside inside is that right am i clear now here effective domain is when ligand binds here now we have discovered that this effector domain does not change the cyclic mp levels directly in between there are many molecular signaling pathways going on right but when ligand bind here there is a change in its internal part right for example this will twist around rather than this form it will change into this form and its effective domain is exposed right previously when it was like this its effective domain was not exposed to the target proteins but when ligand bind here it undergoes a change in such a way that the factor part become more exposed to the next generation of proteins which will interact right so we say a factor do on upon binding with the ligand with the seven pass receptors yes on the ligand binding domain which is extracellular leads to conformational changes in all trans membrane components in such a way that intra cellular component become exposed to the signaling pathways right for example a special protein which will bind with this seven path receptor there's a group of proteins we call them g proteins here i want to remember the just mentioned g proteins are two types of g proteins they're monomeric g proteins mono meric g proteins and there are yes trimeric g protein trimeric g proteins first of all what is g protein g proteins are those proteins which bind gtp or gdp guanosine triphosphate or guanosine diphosphate what are g proteins g proteins are such proteins can bind with gtp or gdp right now if g protein consists of only you can say yes if it consists of only one peptide then g protein is called monomeric but if g protein has three peptides right all of them are making now what is this these are three one two and three three peptides together we call it trimeric protein you must be knowing that they are named as alpha component beta component and gamma component right so g proteins can be monomeric g proteins g proteins can be trimeric g proteins and the g proteins which interact with the seven pass receptors they are actually trimeric g proteins not monomeric g proteins monomers g proteins are having different signaling pathways they do play a role in signaling in the cells but when we talk about seven pass receptors we are talking about those receptors that upon binding with the ligand extracellularly undergo conformational change and intracellularly yes effective domain changes in such a way effector domain changes in such a way that primary g protein will bind there what will bind there trimeric g protein this is alpha component right and here is let's suppose beta and gamma component so basically they expose the site of course when it was if you remove the ligand this will go into this configuration and if it is in this configuration and what do you think now g protein can bind here no so when ligand is removed right then the factor domain become altered in such a way that it is not available to the trimeric intrasolar g proteins but 7 pass receptors whenever they bind with the appropriate ligand which is able to stimulate it able to stimulate the receptors that will eventually lead to change in the molecule in such a way that intracellular part which is effective domain is able to or exposed in such a way that it is able to interact with with g proteins primary g proteins don't say just g proteins say trimeric g protein that is why i said monomeric g proteins have nothing to do with this receptor right is it clear now we know that whole signaling pathway we will discuss later i am just discussing about the broad categories of receptors first category we are talking about those receptors which are expressed on the membrane and they have component passing through the membrane we call them transmembrane receptors we said there are yes one pass receptors classical example is for many growth factors or insulin there are one pass receptors then there are four to five pass receptors which are which are ligand operated ion channels right then there are seven pass receptors right these are the most important receptors why because of presently the drugs which are available in the market right about 30 to 40 drugs act on modifying the actions of seven paths receptors so it's very important to understand these receptors their types and their signaling mechanisms and what biological responses they such receptors produce of course we will discuss in detail later we are just classifying now so we have now we have here seven pass seven pass receptor which are also called serpentine receptors because peptide passes in and out through the membrane in a in a snakey way in a sneaky way seven times right so this is seven pass receptors then there are another group of receptor and mostly students are not aware of that type of receptor another type of receptor present in the membrane yes anyone from here there are yes from there 12 pass receptors very good there are also 12 pass i don't know i shouldn't make more 1 2 3 4 5 6 7 8 9 10 11 and 12 something went wrong because okay so this is 12 pass receptors right these 12 pass receptors also consist of one single peptide chain right and this single peptide chain snakes through or passes through the membrane how many times 12 times right anyone can give me example of such receptors one pass receptor most simple example is insulin or growth factors right four to five pass receptors are ion channels ligand or protein channels seven pass receptors are very commonly for glucagon or adrenergic receptors or some dopaminergic receptors or muscarinic receptors for acetylcholine remember for acetylcholine cholinergic receptors which are ion channel they are also nicotinic receptors are divided into two cholinergic receptors may be nicotinic cholinergic receptors or muscarinic cholinergic receptors nicotinic coral cholinergic receptors are ion channels and muscarinic cholinergic receptors are g protein coupled receptors the seven part receptors are serpentine receptors right ah let's move on and we were talking about that there is 12 pass receptor 10 12 pass receptors yes do you know any example of 12 pass receptors i am not happy with these all the searches they are keep on bringing the new things it was good to be doing the graduation in my time they were not so much knowledge and your time too much knowledge but people who love knowledge it's very lusty development more and more knowledge okay so 12 pass receptors these receptors are usually present on such neurons which release monoamines suppose this is a neuron which release dopamine or epinephrine or norepinephrine for example it is releasing norepinephrine now on the nerve ending there is what is there 12 pass receptor dual pass receptor what is the function of this 12 pass receptor that of course this norepinephrine will act on its receptor on the post synaptic membrane and then some of this norepinephrine is re-uptaken back this reuptake protein right norepinephrine or dopamine or throttling when they are released right they go and act on the postsynaptic membrane produce the biological changes but because these are very precious ligands most of it is taken back and because they are taken back so they are not lost we say that they are reuptaken in the presynaptic membrane and again restored right so this reuptake protein is like scrotum in reuptake protein or norepinephrine reuptake protein or dopamine reuptake proteins these are basically what that do for example scrotum in bind here it undergo the change functional change and throws the dopamine inside you get it so what is this this is the receptor and it passes through the membrane how many times 12 times so 12 pass receptor one of the classical example is those receptors present on the pre-synaptic membrane right on them on the yes mono minergic monoaminergic monoaminergic neurons nerve endings which release monoamine neurotransmitter monoamine neurotransmitter mean neurotransmitters which are derived from one amino acid like epinephrine norepinephrines protein in dopamine right they are monominergic neurons as a group noradrenergic neurons adrenergic neurons dopaminergic neurons certain energy neurons these are all monominergic neurons and this is monomin reuptake system and this reuptake system consists of special transmembrane proteins which are 12 pass receptors is that clear so how many membrane transmembrane proteins are types of receptors are there 12 pass receptor so we have one pass receptor right we have four to five pass receptors right and we have seven pass receptors and we have 12 pass receptors so these receptors are present on the membrane just rapidly tell me yes what is it one path receptors what is might be this four to five pass receptors what it could be seven pass receptors and what could this be twelve pass receptor i have not counted it anyway right so these are classically broad categories of receptors which are present on the membranes on the targets health right then receptors might be present in the cytosol okay they might be present intracellularly also now why some receptors are present intracellularly and why some receptors are present on the membrane answer is very simple those ligands which cannot cross the membrane they should have receptor on the membrane those ligands which cannot cross the membranes they must have receptors on the membrane so usually these receptors which are on the membrane their ligands are either highly polar or molecularly large so if they're large molecule or highly polar charged molecule they cannot pass through the membrane as they cannot pass through the membrane like epinephrine norepinephrine dopamine rotanine histamine these are charged molecule they cannot cross through the membranes so their receptors should be on the cell membrane in the same way if we talk about insulin or glucagon or ah follicle stimulating hormone or luteinizing hormone these are peptides peptide also cannot cross their significantly larger molecule simply they cannot go through the membrane so their receptors should be present on the cell membrane but there are some substances which can cross the cell membrane and go inside it is very natural if someone cannot come inside your house and he has to give some message he will knock on the door but some member of your family will simply walk in right similarly some ligands can simply walk in diffusions inside the cells for example uh these substances are either very small or they're lipid soluble so they can pass through the bi lipid lipid bilayer right classically here i can say like estrogen receptor estrogen can go inside the cell in the same way t3 thyroid hormone now estrogen can easily go inside the cell or tyrosine is significantly small molecule can uh t3 significantly small molecule can go inside and estrogen of course it is derived from the modifications over the cholesterol molecule which is lipid soluble can go inside the cells so such molecules or even vitamin d3 right so such molecules they are receptors aware intracellular now these intracellular receptors right for example for estrogen and t3 if you focus just for these two examples they can be present in cytosol or they can be present inside the nucleus and the receptors are present on the dna the receptors are dna dna right for example dna act as receptors for alkylating agent anti-cancer drugs now estrogen has receptors okay i will just try to confuse you let's see what happen you get confused or not let me try estrogen receptors is in cytosol or in the nucleus actually estrogen receptor is cytosolic receptor or intra nuclear receptor and other question is t3 receptors are primarily located in the cytosol or inside the nucleus do you have an answer yes my question is very simple that estrogen receptors and t3 receptors both of them are intracellular one of them have receptor in the cytosol otherwise receptor in the nucleus how you can guess it it's very simple this is coming from thyroid when you talk about t3 what do you think of which gland thyroid and when you talk about estrogen the most visible sign of estrogen is what breast estrogen progesterone act on the breast is that right yes yes clear when you would think of estrogen estrogen has many function but at least you should remember development of breast right and t3 whenever you think your mind should go to which hormone a gland thyroid now you tell me breast well fully developed breast is bigger or thyroid gland is bigger normal thyroid gland is bigger or normal breast is bigger mess is bigger so breast should be now it is a little naughty thing that should be in the cytosol or in the nucleus cytosol and if it is in the cytosol of course it is not there just remember so estrogen receptors are in the cytosol estrogen receptors are in cytosol right just it is to remember and t3 t4 receptors especially t3 which is active form its receptor should be nucleus right t3 receptors right so what we have discussed that there are receptors which are cellular receptors and extracellular receptors cellular receptors may be transmembrane receptors or membranous receptors and there can be cytosolic receptors or there can be nuclear receptors classically they are broadly speaking broadly speaking there are four categories of membrane receptors they are one pass receptors four to five pass receptors seven pass receptors twelve pass receptors and when we talk about intracellular receptors there are so many examples but we just talk about two estrogen receptors and t3 receptors estrogen receptors are present in cytosol and t3 receptors are present in nucleus right and easy way to remember is that usually fully developed breast is larger than fully developed thyroid gland so cytosol is a bigger space which can accommodate the breast it is just your imagination and nucleus is smaller space which can accommodate thyroid gland but actually we are talking about referring to not thyroid gland we are referring to t3 receptors here we are really not talking about putting the breasts in cytosol we are talking about estrogen receptors in cytosol when estrogen come it will meet its receptor in cytosol on the target cell then receptor estrogen complex will move to the nucleus and bring alter the expression of genes is that right now we are left with the last category of receptors which are extracellular receptors it means there are some macromolecules or complex of macromolecules which are outside the cells in extracellular space and they also do respond to ligands and bring biological changes in the system right so you can tell me any extra cellular receptors yes doctor okay actually coagulation factor we can say coagulation factors many drugs interact with coagulation factors and alter the function of the coagulation factor so coagulation factors are extracellularly they are present in plasma is that right in the blood or for example hyperinacton yes antithrombin 3 so that is extra cellular proteins right the function of anti-thrombin 3 is that it inactivates some of the activated coagulation factors especially activated 10 factor right and some other so actually what happens that some of the coagulation factors of course uh coagulation factors are outside the cells and some drugs binds with coagulation factors in such a way that coagulation factors function is altered either their function is prolonged or the function is reduced or what happens let me tell you suppose this is antithrombin 3 what is this antithrombin 3 molecule right this is extracellular and here what minds here heparin when happening bind on this point of anti-thrombin 3 this is ligand binding domain but when heparin bind over here and disturb the tail it must become more active to destroy the destroy the coagulation factors this is active calculation factor and here are pieces of it so what happens heparin binding domain is present on anti-thrombin 3 and this is lagging binding domain hyperin-binding domain and this is the factor domain so once the ligand or hyperin binds with the what is this antithrombin three antithrombin three molecules capability to inactivate the activated coagulation factor is enhanced so this must be effective domain you are getting it yes so what we can say some of the coagulation factors which can bind with the drugs or bind with the certain uh you can say endogenous substances and undergo altered function we can consider them as receptors like antithrombin 3 is considered receptor for hyperine in the same way some drugs act act on the activated activated complement proteins like c5a some drugs act on c complement 5a right and alter the function of c5a so that will be what extracellular receptor in the same way there are many drugs now coming which act on the antibodies there are many drugs which interact with the antibodies and alter the function of the antibodies let's suppose this is an antibody suppose drug binds here and here and alter the function of antibody right so in this case this will be ligand binding domain this will be effective domain you are getting it so what we can say that actually some of the receptors or macromolecules are present outside the cells we call them extracellular receptors these extracellular receptors right these extracellular receptors right classically there may be coagulation factors or they may be yes antibodies or they might be cytokines very good very good cytokines or they might be activated c5a right so drugs which are acting with these molecules and bringing the changes in them in their functional changes right we say that drugs are acting as ligand and these proteins extracellular protein when bind with the ligand they produce a biological response altered response so these proteins are behaving as receptors let's sum it up what is the receptor receptors are basically two types they're sensory receptors and biochemical or pharmacological receptors sensitive receptors are related with central nervous system and picking up different sensations we will not talk about that today today we will focus on which kind of receptors pharmacological or biochemical or bio receptors in biochemistry or receptors in the physiology or receptor then pharmacology right especially this group of receptors we call them that these are all macromolecules usually they are protein but they may not be protein for example some act on dna so dn is a macromolecule so what is a receptor receptor is a macromolecule or a complex of macromolecule which should have at least two functional domain ligand binding domain and effector domain is that right yes number one number two receptor types and sites receptors are present cellularly and extracellularly cellular receptor first because they're more abundant cellular receptors are membranous receptors which are usually transmembrane proteins and then there are cytosolic receptors and there are intra nuclear receptors classically speaking membranous receptors have four broad categories yes one pass receptors four to five pass receptors seven pass receptors per pass receptor very good these are membranous receptors right one path receptor classical example is like for insulin or like for different growth factors five past four to five past receptors are uni iron channels which alter the function of binding of specific ligand and seven pass receptors are intracellularly coupling with g proteins so seven pass receptors are also called g protein coupled receptors right they coupled with that primary g protein not with monomeric g proteins they coupled with trimeric g proteins not with the monomeric g proteins and uh after seven pass receptors we come to what are these twelve pass receptors twelve past receptors are found specially in uh those new nerve endings pre-synaptic nerve endings uh those nerves which are monominergic right menorrhagic nerve endings which release epinephrine norepinephrine or dopamine or srotanine what is the function of this 12-pass receptor the they act as a re-uptake mechanism for the released neurotransmitter right some of the neurotransmitter will diffuse away and that will be catabolized somewhere in the body but much of it will be re-uptaken right and why why i call it receptor because some drugs can work over here number one for example scrotanin can bind here five hydroxy tryptamine that can bind here and that is taken from extracellularly transported by the receptor intersectionally and maybe might be it is stored again number two some drugs can bind with these receptors throttling re-uptake inhibitors like fluoxetine so fluoxetine is working on what kind of receptors 12 pass receptors right so let's take a break and then we'll continue any question you have sir we have discussed that t3 receptors are intra-nuclear what about a4 actually most of the t4 harmon before it enter into cell is converted into t3 and t3 is the active form so we are more concerned about d3 receptor is that right thank you very much class dismiss after this in the next lecture we will be talking about in detail g protein coupled receptors and then of course g protein coupled receptors ligand binding domain in the next lecture especially i will define and differentiate agonist antagonists which are easy to easy concept and real concept which i will explain is partial agonist antagonist molecules partial agonist antagonist molecule right or drugs then i'll talk about transmembrane domain effector domain actions and functions of yes of seven pass receptors then how they activate the g proteins what is the exact mechanism how g proteins bind with the effector domain of seven pass receptors and then i will discuss very important thing how these receptors can be inactivated seven path receptors or they can be desensitized or re-sensitized or downregulated or upregulated we'll talk about these concepts in coming lectures class dismiss thank you very much

today we are going to talk about g protein coupled receptors g protein coupled 
receptors which are also called seven pass   receptors and which are also called serpentine 
receptors because they seven time passes the   membrane and look like a sneaky shape like a 
snake right so wherever in the literature medical   literature you study g protein coupled receptor 
or seven path receptor or serpentine receptor they   are one and the same thing right but before really 
i in this lecture what we will be doing first of   all we will discuss about the structure of the 
receptor how this receptor is structured what   are important domains like right and then we&#39;ll 
talk about activation and function of the receptor   after that will go how these receptors are 
activated and how these are inactivated   right and what is the difference between 
inactivation of receptor and desensitization   and how receptors undergo desensitization 
and how receptors can be re-sensitized   and then we will talk about down regulation 
of seven path receptors and up regulation   of seven pass receptors because why i included 
especially this component because many students   get confused about inactivation of receptors or 
desensitization of receptors or down regulation   of receptor but today we will try our best to 
make it crystal clear differences among these   conditions right so before really i discuss g 
protein coupled receptor let me discuss about   basic concept that what is receptor right 
what is receptor receptor is actually   uh we are uh there are two types of 
receptors they are sensory receptors   sensory receptors which are related with 
especially with the neurological system   right there are sensory receptors like uh taste 
buds like rods and cones right like pacinian   corpuscles these are sensory receptors we will not 
talk about these receptors today we will not talk   about sensory receptors today our discussion 
is about those receptors those macromolecules   right which are specially related with physiology 
biochemistry and pharmacology right so we will   limit ourselves to those receptors which 
are specially involved in biological system   related with physiology biochemistry and 
especially pharmacology right now what is receptor   receptor is any macromolecule what it is 
it is any macromolecule macro molecule or   complex of macromolecules 
complex of macro molecules right in old time we used to say that such 
receptors are generally protein receptors   yes this is right generally these receptors are 
proteins or peptides but some of the receptors   are not proteins or peptides like dna dna is a 
macromolecule of course it is not protein and some   of the drugs directly act on the dna for example 
alkylating agents right anti-cancer drug some of   the anti-cancer drugs directly act on the dna so 
for those drugs dna itself is a receptor right   that is why now we have changed the definition 
we don&#39;t say that receptors are proteins   we say they are macromolecules which 
may be proteins which might be dna or   that might be rna or any other big molecule 
or complexes of big molecules is that right so   receptors are macromolecules or complexes of 
macromolecules which have special two functions   they should have at least two two functions 
or rather i should say two functional domains   they should have two functional domains right two 
functional domain mean there should be one domain   for example if this is a receptor let&#39;s 
suppose this is a receptor right and okay now if this is a receptor one one side of 
the receptor one domain of the receptor should be   such that where a specific molecule can bind 
and that molecule which can bind here let&#39;s   suppose this is the molecule which can bind here 
such molecule would bind with a special domain   specific domain of a receptor such molecule is 
called ligand binding domain what is this this is   ligand binding domain how we 
define ligand ligand is a substance   which binds with the receptor and brings 
the conformational or functional change in   the structural and functional change in the 
receptor to produce some biological response what is likened ligand is the substance which bind 
with the receptor where it binds with the receptor   at the ligand binding domain at the ligand 
binding domain right and once it bind here it   is just like this you irritate my pull my ear and 
i will you might kick you if you pull my ear so   your hand is the ligand my ear is the lag 
and binding domain and the kick i do or   response i do that is biological response is that 
right okay for this simple thing we can save a   ligand bind over here right whenever it brings 
its tongue and start testing the things around so it is other functional domain 
first domain was ligand binding domain   right second domain is effector domain what 
is that okay i will make it like again this is   okay specifically what is this ligand binding 
domain right where you can bind some ligand now this ligand may be a hormone 
maybe a neurotransmitter may be a drug   right yes so many so hormones or 
neurotransmitter or drugs they usually   go and bind with the receptor at which domain 
ligand binding domain and in response to that   binding receptor undergo a conformational 
change under structural and functional   change it undergoes a modification and 
result of that modification will be that when it binds ligand binds and other 
domain is activated right or inactivated   there is some change right this 
changes this domain is called effector   domain factor domain so basically what is 
receptor receptor is a macromolecule or a   complex of macro molecule right which it should 
have at least two minimum functional domains   two functional areas one like and finding domain 
other effector domain you remain remove it   tango in you put it here tongue comes out 
right so you understand it so is that clear now i will ask a question to you plasma 
proteins they bind many things   plasma proteins like albumin pre albumin and 
others they bind many hormones and even they   bind very many many drugs are plasma proteins 
receptors yes doctor they are receptors okay   do you what do you think they are receptor 
or not receptor say yes or no no confusion   no why they are not receptors 
they are binding a substance he is saying that plasma protein okay 
let&#39;s suppose here is a plasma protein   plasma protein may bind many things but it does 
not under it does have binding domain but does   not have a factor domain plasma proteins 
do bind many substances but plasma proteins   once they bind a substance usually they 
don&#39;t undergo any conformational change   and they don&#39;t have any effectors a factor 
domain and usually when substances bind with   the plasma proteins they do not produce any 
special or specific biological response so   it is just like that that plasma protein is that 
you are doing like this but there is no response so just have so everything which in the 
our body every macro molecule in our body   which can bind something right but does not 
undergo any conformational change and then   does not produce any effector biological 
response that thing cannot be called receptor   so plasma proteins are just carrier of hormones 
or carrier of drugs or we can say they are drug   binding they are binding to the hormones and many 
substances but plasma proteins do not produce   once the substance bind with the plasma 
protein usually plasma protein do not   produce any specific response so what i 
want to hammer in your mind that to be a   receptor it should have minimum to minimum two 
domains two special points at its number one   two special qualities number one lag and binding 
domain and affected domain an effect is produced   is that clear right now there are many types of 
receptors right we are again i&#39;m saying that we   are concentrating only on the biochem receptors in 
biochemistry and pharmacology physiology right now receptors are many types of the receptors i 
will just talk about their broad categories   and then i will go back in detail of g protein 
coupled receptors yes you have a question uh yes   sir actually you say that the receptor binds and 
then produces a biological response so when this   response be limited to the cells only or will it 
go through the whole system i&#39;m going to tell you   actually he asked me a very important question he 
says that uh when lagging bind with the receptor   and i&#39;m saying that there&#39;s a biological response 
is is this biological response only on cell answer   is that if it is a cellular receptor if it is on 
cell membrane or receptor is in the cytosol or   receptors in the nucleus then of course there 
will be change in the cell but if many change   many cells undergo changes of course that may 
produce some biological response which might be   cellular or might be systemic right multisystem 
like adrenaline epinephrine norepinephrine   when the epinephrine norepinephrine is injected 
in the body or dopamine their receptors are   present on multi organs and multi systems 
so they will bring the changes in cells of   multiple organs and systems and multisystemic 
response can come so minimum receptor   upon binding with the ligand can produce cellular 
changes and maximum it can produce multiple   multi-systemic biological changes it depends 
on what is the ligand ligand and what is the   distribution of the receptors on the 
tissues and how they are responding   is that right let&#39;s come back that 
these receptors where they are located   let me let me make a cell here suppose this is 
a cell now okay let me make it a bigger cell let&#39;s suppose this is cell membrane 
and here is the nucleus right now   what could be the location of the receptors there 
are some locations almost every student know and   there is one location usually student 
forget right let me tell you the common locations number one is cell membrane some of the 
receptors are macromolecules usually proteins with   some oligosaccharides which are present in the 
membrane we call them transmembrane receptors   or they are integral proteins right then there 
are some receptors which are in the cytosol right and there are some receptors 
which have which are present in the   nucleus right and there is one more site where 
their receptor can be these are cellular receptor   the cellular receptor might be on the mem inserted 
on the membrane or appearing on the membrane or   they may be in the cytosol or even they might 
be in the nucleus i will give you examples but   tell me one more site any one of these front boys 
yes anymore site where receptors can be present   where receptors can be present 
that is that is yes yes yes come on   that is extracellular site some 
macromolecules are outside the   cells or you can say in extracellular 
space or in between the cells and some macromolecules are outside the cells 
and sometimes some substances bind with them   and bring the change into that molecule due to 
effector activity and change biological system you   must be thinking what is this you must be thinking 
but i will not tell you now first i will tell you   these common three things and then you have to 
ask me remind me to tell extracellular receptors   right okay let&#39;s start with generally general 
categories main categories of membranous receptors   right membranous receptors are number one yes 
one pass receptors one path receptors are having   lag and binding domain outside effector domain 
inside and one time they pass through the membrane   right so this is a peptide let&#39;s suppose this is a 
peptide where it binds the ligand outside the cell   right ligand binding domain is extracellular and 
effector domain is intracellular and one part   is passing through the membrane which is called 
trans membrane part so this strip this receptor   has one ligand binding domain one effector 
domain and in between there is trans membrane   component so trans membrane component outside bind 
with ligand binding domain and inside it is having   a factor domain so when ligand 
bind with extracellular area   inter solar start some activity or some biological 
change or some signaling inside in this way   these receptors which we call them transmembrane 
receptors this whole group is responsible for   taking the extra cellular signals right and and 
under the signals they bring intracellular change   they bring biological response inside the cell 
right they bring alteration in the cell now now   this is how many pass one pass receptor so we can 
say this is one pass receptor classical example of   one path receptors are tyrosine kinase receptors 
insulin receptor yes very good insulin receptor is   one pass receptor but let me tell you something 
interesting when insulin binds with the receptor   other receptors also come so two receptors with 
one insulin two one pass receptors bind with that   and that is dimerization that for example this 
is one pass receptor if insulin bind here it will   also bring one more one pass receptor right and 
two one pass receptors will make a dimer and that   dimer will that dimer will bring intracellular 
changes on the target cells but anyway   this is an example of what one pass receptor 
then there are receptors which are usually   of course they consist of peptide chains most 
of the receptors which are on the membrane they   are peptide chains one peptide chain or more than 
one peptide there are receptors which are not one   pass receptor there are more pass receptors like 
four to five pass receptors there can be four to   five pass receptors there may be four or 
five different peptide units which are going   through the membrane or there is one peptide 
unit but passes through four or five times   can you tell me some example of such a receptors 
yes yes doctor any receptor where peptide unit is   the peptide unit is passing through the membrane 
four or five times right are you going to tell me   yes ion channels very good for example ligand 
binding ion channels let&#39;s suppose this is yes this let&#39;s suppose this is called 
energic receptors cholinergic   nicotinic receptors acetylcholine will 
bind here acetal choline will bind here   right so this will be ligand binding domain 
and when it binds here let&#39;s suppose it   changes the frequency of opening and 
closing of this receptors so this   tunnel through which this tunnel opens and 
close this canal which opens and close closes   this canal is basically yes this canal okay 
let me tell you exactly this is acting as what   a factor component so upon like by ligand 
binding right upon ligand binding some ion channels undergo conformational change and 
that alters the flux of movement of the ions   right so we call such receptors as yes ligand yes 
no no these are ion channels but they are operated   by ligand binding so ligand gated ion channels 
or ligand operated ligand operated ion channels   such ion channels where function depend on 
the presence of the ligand and effector unit   is basically a canal right a central pore which is 
opening extracellularly as well as intracellularly   and when ligand binds uh basically opening and 
closing of ah frequency of these canal changes   and that brings the biological changes right then 
there are so this is how many four to four to five   pass receptors then with we come to our beloved 
receptors the most loved one receptors even though   they look like snake serpentine receptors they 
pass through the membrane seven times we call them   seven pass receptors and let me draw here 
uh here is seven pass receptor let&#39;s suppose   this is one peptide it is just one peptide chain 
but it passes through the membrane seven times   now because this peptide chain is passing 
through the membrane seven times one   two three four five six and seven due 
to this reason simply they are called   seven pass receptors when they were discovered 
initially that researchers found there is a   peptide there are peptides in the membranes 
which pass through the membrane seven time and   they thought when a ligand bind here some changes 
are in the cell so they said that this is seven   pass receptors right in those days they only 
knew for example if adrenaline binds here right   this change in for example cyclic 
amp levels doctors there was so if   catecholamines adrenaline or noradrenaline bind 
with its with its seven past adrenergic receptor   there is intracellular change in cyclic emp 
levels in in those days many decades back in   between what was happening we were not knowing 
we were just knowing this thing the adrenaline   bind with the ligand binding domain and somehow 
in the cell what happens cyclic amp levels change   is that right so then doctors called adrenaline or 
such molecules first messenger or molecules which   were changing in the cell which doctors were able 
to measure they call this that second messenger   that is why neurotransmitters or hormones or drugs 
they are actually when they go and bind with the   ligand binding domain we say first 
messenger has arrived and ultimate   biological change which is coming into cell 
right in the special molecules we call them   second messenger but now over the years we have 
discovered there are so many things in between   for example when ligand binds here right this 
is ligand binding domain and what is this domain   transmembrane domain and what is this domain   effector domain right now we have discovered again 
i will repeat it what is it what is this component   lag and binding domain and what is this 
component effector effector domain this is factor effector domain and 
this is ligand binding domain   and this peptide has one pocket outside 
where ligand can bind specific ligand and one   tail inside right usually this peptide 
has a minor end outside and three terminal   inside is that right you know peptide 
chain has two ends a minor end and   carboxylic carboxylate so what happens these 
peptide chains when they passes through the   membrane seven time they are always keeping 
amino and outside and they are keeping the   carboxylate inside so we say amino terminus is 
outside extracellular and what is this terminal   carboxylic terminal terminal inside inside is 
that right am i clear now here effective domain is   when ligand binds here now we have discovered 
that this effector domain does not change   the cyclic mp levels directly in between there 
are many molecular signaling pathways going on   right but when ligand bind here there is a change 
in its internal part right for example this will   twist around rather than this form it will change 
into this form and its effective domain is exposed   right previously when it was like this its 
effective domain was not exposed to the target   proteins but when ligand bind here it undergoes a 
change in such a way that the factor part become   more exposed to the next generation 
of proteins which will interact   right so we say a factor do on upon binding 
with the ligand with the seven pass receptors   yes on the ligand binding domain which is 
extracellular leads to conformational changes   in all trans membrane components in such 
a way that intra cellular component become   exposed to the signaling pathways right 
for example a special protein which will   bind with this seven path receptor there&#39;s 
a group of proteins we call them g proteins   here i want to remember the just mentioned g 
proteins are two types of g proteins they&#39;re   monomeric g proteins mono meric g proteins and 
there are yes trimeric g protein trimeric g   proteins first of all what is g protein 
g proteins are those proteins which bind gtp or gdp guanosine triphosphate or guanosine 
diphosphate what are g proteins g proteins are   such proteins can bind with gtp or gdp 
right now if g protein consists of only   you can say yes if it consists of only 
one peptide then g protein is called   monomeric but if g protein has three peptides right all of them are making now 
what is this these are three one   two and three three peptides together we 
call it trimeric protein you must be knowing   that they are named as alpha component 
beta component and gamma component right so   g proteins can be monomeric g proteins g 
proteins can be trimeric g proteins and the   g proteins which interact with the seven pass 
receptors they are actually trimeric g proteins   not monomeric g proteins monomers g proteins are 
having different signaling pathways they do play   a role in signaling in the cells but when we talk 
about seven pass receptors we are talking about   those receptors that upon binding with the ligand 
extracellularly undergo conformational change and   intracellularly yes effective domain changes in 
such a way effector domain changes in such a way   that primary g protein will bind there 
what will bind there trimeric g protein   this is alpha component right and here is let&#39;s 
suppose beta and gamma component so basically   they expose the site of course when it was if 
you remove the ligand this will go into this   configuration and if it is in this configuration 
and what do you think now g protein can bind here   no so when ligand is removed right 
then the factor domain become   altered in such a way that it is not 
available to the trimeric intrasolar   g proteins but 7 pass receptors whenever 
they bind with the appropriate ligand   which is able to stimulate it able to 
stimulate the receptors that will eventually   lead to change in the molecule in such a way 
that intracellular part which is effective domain   is able to or exposed in such a way 
that it is able to interact with   with g proteins primary g proteins don&#39;t 
say just g proteins say trimeric g protein   that is why i said monomeric g proteins 
have nothing to do with this receptor   right is it clear now we know that whole 
signaling pathway we will discuss later i am   just discussing about the broad categories of 
receptors first category we are talking about those receptors which are expressed on the 
membrane and they have component passing   through the membrane we call them transmembrane 
receptors we said there are yes one pass receptors   classical example is for many growth factors 
or insulin there are one pass receptors   then there are four to five pass receptors 
which are which are ligand operated ion channels   right then there are seven pass receptors right 
these are the most important receptors why because   of presently the drugs which are available in 
the market right about 30 to 40 drugs act on   modifying the actions of seven paths receptors so 
it&#39;s very important to understand these receptors   their types and their signaling mechanisms and 
what biological responses they such receptors   produce of course we will discuss in detail later 
we are just classifying now so we have now we have   here seven pass seven pass receptor which are 
also called serpentine receptors because peptide   passes in and out through the membrane 
in a in a snakey way in a sneaky way   seven times right so this is seven pass receptors 
then there are another group of receptor and   mostly students are not aware 
of that type of receptor   another type of receptor present in the membrane 
yes anyone from here there are yes from there   12 pass receptors very good there are also 
12 pass i don&#39;t know i shouldn&#39;t make more 1   2 3 4 5 6 7 8 9 10 11 and 12 something went wrong 
because okay so this is 12 pass receptors right   these 12 pass receptors also consist of one single 
peptide chain right and this single peptide chain   snakes through or passes through the 
membrane how many times 12 times right   anyone can give me example of 
such receptors one pass receptor   most simple example is insulin or growth factors 
right four to five pass receptors are ion channels   ligand or protein channels seven pass receptors 
are very commonly for glucagon or adrenergic   receptors or some dopaminergic receptors or 
muscarinic receptors for acetylcholine remember   for acetylcholine cholinergic receptors which are 
ion channel they are also nicotinic receptors are   divided into two cholinergic receptors may be 
nicotinic cholinergic receptors or muscarinic   cholinergic receptors nicotinic coral 
cholinergic receptors are ion channels   and muscarinic cholinergic receptors are g protein 
coupled receptors the seven part receptors are   serpentine receptors right ah let&#39;s move on and we 
were talking about that there is 12 pass receptor   10 12 pass receptors yes do you know 
any example of 12 pass receptors   i am not happy with these all the searches 
they are keep on bringing the new things   it was good to be doing the graduation in 
my time they were not so much knowledge   and your time too much knowledge but people 
who love knowledge it&#39;s very lusty development   more and more knowledge okay so 12 pass 
receptors these receptors are usually present on   such neurons which release monoamines suppose this 
is a neuron which release dopamine or epinephrine   or norepinephrine for example it is releasing 
norepinephrine now on the nerve ending there is   what is there 12 pass receptor dual pass receptor 
what is the function of this 12 pass receptor that of course this norepinephrine will act on 
its receptor on the post synaptic membrane   and then some of this norepinephrine is 
re-uptaken back this reuptake protein right   norepinephrine or dopamine or throttling when 
they are released right they go and act on the postsynaptic membrane produce the biological 
changes but because these are very precious   ligands most of it is taken back and because 
they are taken back so they are not lost we say   that they are reuptaken in the presynaptic 
membrane and again restored right so this   reuptake protein is like scrotum in reuptake 
protein or norepinephrine reuptake protein   or dopamine reuptake proteins these are basically 
what that do for example scrotum in bind here   it undergo the change functional change and 
throws the dopamine inside you get it so what   is this this is the receptor and it passes through 
the membrane how many times 12 times so 12 pass   receptor one of the classical example is those 
receptors present on the pre-synaptic membrane   right on them on the yes mono minergic 
monoaminergic monoaminergic neurons nerve endings   which release monoamine neurotransmitter monoamine 
neurotransmitter mean neurotransmitters which are   derived from one amino acid like epinephrine 
norepinephrines protein in dopamine right they   are monominergic neurons as a group noradrenergic 
neurons adrenergic neurons dopaminergic neurons   certain energy neurons these are all monominergic 
neurons and this is monomin reuptake system   and this reuptake system consists of special 
transmembrane proteins which are 12 pass receptors   is that clear so how many membrane transmembrane 
proteins are types of receptors are there   12 pass receptor so we have one pass receptor 
right we have four to five pass receptors right   and we have seven pass receptors and we have 
12 pass receptors so these receptors are   present on the membrane just 
rapidly tell me yes what is it one path receptors what is might 
be this four to five pass receptors   what it could be seven pass 
receptors and what could this be twelve pass receptor i have not counted it anyway 
right so these are classically broad categories of   receptors which are present on the membranes 
on the targets health right then receptors   might be present in the cytosol okay they 
might be present intracellularly also now why some receptors are present intracellularly 
and why some receptors are present on the membrane   answer is very simple those ligands which cannot 
cross the membrane they should have receptor   on the membrane those ligands which cannot 
cross the membranes they must have receptors   on the membrane so usually these receptors which 
are on the membrane their ligands are either   highly polar or molecularly large so if they&#39;re 
large molecule or highly polar charged molecule   they cannot pass through the membrane as they 
cannot pass through the membrane like epinephrine   norepinephrine dopamine rotanine histamine these 
are charged molecule they cannot cross through the   membranes so their receptors should be on the 
cell membrane in the same way if we talk about   insulin or glucagon or ah follicle stimulating 
hormone or luteinizing hormone these are peptides   peptide also cannot cross their 
significantly larger molecule   simply they cannot go through the membrane 
so their receptors should be present on the   cell membrane but there are some substances 
which can cross the cell membrane and go inside   it is very natural if someone cannot come 
inside your house and he has to give some   message he will knock on the door but some 
member of your family will simply walk in   right similarly some ligands can simply walk 
in diffusions inside the cells for example   uh these substances are either very small or 
they&#39;re lipid soluble so they can pass through   the bi lipid lipid bilayer right classically 
here i can say like estrogen receptor estrogen   can go inside the cell in the same way t3 thyroid 
hormone now estrogen can easily go inside the cell   or tyrosine is significantly small molecule can 
uh t3 significantly small molecule can go inside   and estrogen of course it is derived from the 
modifications over the cholesterol molecule   which is lipid soluble can go inside the cells so 
such molecules or even vitamin d3 right so such   molecules they are receptors aware intracellular 
now these intracellular receptors right for   example for estrogen and t3 if you focus just for 
these two examples they can be present in cytosol   or they can be present inside the nucleus and the 
receptors are present on the dna the receptors are   dna dna right for example dna act as receptors 
for alkylating agent anti-cancer drugs now estrogen has receptors okay i will just 
try to confuse you let&#39;s see what happen   you get confused or not let me try estrogen 
receptors is in cytosol or in the nucleus actually   estrogen receptor is cytosolic receptor or 
intra nuclear receptor and other question is   t3 receptors are primarily located in the cytosol 
or inside the nucleus do you have an answer yes my question is very simple that 
estrogen receptors and t3 receptors   both of them are intracellular one 
of them have receptor in the cytosol   otherwise receptor in the nucleus how you can 
guess it it&#39;s very simple this is coming from   thyroid when you talk about t3 what do you think 
of which gland thyroid and when you talk about   estrogen the most visible sign of estrogen is what 
breast estrogen progesterone act on the breast   is that right yes yes clear when you would think 
of estrogen estrogen has many function but at   least you should remember development of breast 
right and t3 whenever you think your mind should   go to which hormone a gland thyroid now you tell 
me breast well fully developed breast is bigger   or thyroid gland is bigger normal thyroid gland is 
bigger or normal breast is bigger mess is bigger   so breast should be now it is a little naughty 
thing that should be in the cytosol or in the   nucleus cytosol and if it is in the cytosol of 
course it is not there just remember so estrogen   receptors are in the cytosol estrogen receptors 
are in cytosol right just it is to remember and   t3 t4 receptors especially t3 which is active 
form its receptor should be nucleus right t3 receptors right so what we have discussed that 
there are receptors which are cellular receptors   and extracellular receptors cellular receptors may 
be transmembrane receptors or membranous receptors   and there can be cytosolic receptors or there 
can be nuclear receptors classically they are   broadly speaking broadly speaking there are four 
categories of membrane receptors they are one   pass receptors four to five pass receptors seven 
pass receptors twelve pass receptors and when we   talk about intracellular receptors there are so 
many examples but we just talk about two estrogen   receptors and t3 receptors estrogen receptors are 
present in cytosol and t3 receptors are present in   nucleus right and easy way to remember is that 
usually fully developed breast is larger than   fully developed thyroid gland so cytosol is a 
bigger space which can accommodate the breast   it is just your imagination and nucleus is smaller 
space which can accommodate thyroid gland but   actually we are talking about referring to not 
thyroid gland we are referring to t3 receptors   here we are really not talking about putting the 
breasts in cytosol we are talking about estrogen   receptors in cytosol when estrogen come it will 
meet its receptor in cytosol on the target cell   then receptor estrogen complex will move to the 
nucleus and bring alter the expression of genes is   that right now we are left with the last category 
of receptors which are extracellular receptors   it means there are some macromolecules 
or complex of macromolecules which are   outside the cells in extracellular space and 
they also do respond to ligands and bring   biological changes in the system right so 
you can tell me any extra cellular receptors yes doctor okay actually coagulation factor we can say 
coagulation factors many drugs interact with   coagulation factors and alter the function of 
the coagulation factor so coagulation factors are   extracellularly they are present in 
plasma is that right in the blood or   for example hyperinacton yes antithrombin 3 so 
that is extra cellular proteins right the function   of anti-thrombin 3 is that it inactivates 
some of the activated coagulation factors   especially activated 10 factor right 
and some other so actually what happens   that some of the coagulation factors of course 
uh coagulation factors are outside the cells and   some drugs binds with coagulation factors in such 
a way that coagulation factors function is altered   either their function is prolonged or the function 
is reduced or what happens let me tell you suppose this is antithrombin 3 what is this antithrombin 3 
molecule right this is extracellular and here what   minds here heparin when happening bind on this 
point of anti-thrombin 3 this is ligand binding   domain but when heparin bind over here and disturb 
the tail it must become more active to destroy the destroy the coagulation factors this is active 
calculation factor and here are pieces of it so   what happens heparin binding domain is present 
on anti-thrombin 3 and this is lagging binding   domain hyperin-binding domain and this is 
the factor domain so once the ligand or   hyperin binds with the what is this antithrombin 
three antithrombin three molecules capability to   inactivate the activated coagulation factor 
is enhanced so this must be effective domain   you are getting it yes so what we can say some 
of the coagulation factors which can bind with   the drugs or bind with the certain uh you 
can say endogenous substances and undergo   altered function we can consider them as receptors   like antithrombin 3 is considered receptor 
for hyperine in the same way some drugs act   act on the activated activated complement proteins 
like c5a some drugs act on c complement 5a right   and alter the function of c5a so that will 
be what extracellular receptor in the same   way there are many drugs now coming which 
act on the antibodies there are many drugs   which interact with the antibodies and 
alter the function of the antibodies   let&#39;s suppose this is an antibody suppose drug 
binds here and here and alter the function of   antibody right so in this case this will be ligand 
binding domain this will be effective domain   you are getting it so what we can say that 
actually some of the receptors or macromolecules   are present outside the cells we call them 
extracellular receptors these extracellular   receptors right these extracellular receptors 
right classically there may be coagulation factors   or they may be yes antibodies or they might 
be cytokines very good very good cytokines or   they might be activated c5a right so drugs which 
are acting with these molecules and bringing the   changes in them in their functional changes 
right we say that drugs are acting as ligand   and these proteins extracellular protein 
when bind with the ligand they produce a   biological response altered response so 
these proteins are behaving as receptors   let&#39;s sum it up what is the receptor receptors 
are basically two types they&#39;re sensory receptors   and biochemical or pharmacological receptors 
sensitive receptors are related with central   nervous system and picking up different 
sensations we will not talk about that today   today we will focus on which kind of receptors 
pharmacological or biochemical or bio receptors   in biochemistry or receptors in the physiology 
or receptor then pharmacology right especially   this group of receptors we call them that these 
are all macromolecules usually they are protein   but they may not be protein for example 
some act on dna so dn is a macromolecule   so what is a receptor receptor is a macromolecule 
or a complex of macromolecule which should have at   least two functional domain ligand binding domain 
and effector domain is that right yes number one   number two receptor types and sites receptors 
are present cellularly and extracellularly   cellular receptor first because they&#39;re more 
abundant cellular receptors are membranous   receptors which are usually transmembrane proteins 
and then there are cytosolic receptors and there   are intra nuclear receptors classically speaking 
membranous receptors have four broad categories   yes one pass receptors four to five pass receptors 
seven pass receptors per pass receptor very good   these are membranous receptors right one path 
receptor classical example is like for insulin   or like for different growth factors five past 
four to five past receptors are uni iron channels   which alter the function of binding of 
specific ligand and seven pass receptors are   intracellularly coupling with g proteins so seven 
pass receptors are also called g protein coupled   receptors right they coupled with that primary g 
protein not with monomeric g proteins they coupled   with trimeric g proteins not with the monomeric 
g proteins and uh after seven pass receptors   we come to what are these twelve pass receptors 
twelve past receptors are found specially in uh   those new nerve endings pre-synaptic nerve 
endings uh those nerves which are monominergic   right menorrhagic nerve endings which release 
epinephrine norepinephrine or dopamine or   srotanine what is the function of this 12-pass 
receptor the they act as a re-uptake mechanism   for the released neurotransmitter right some 
of the neurotransmitter will diffuse away and   that will be catabolized somewhere in the body 
but much of it will be re-uptaken right and why   why i call it receptor because some drugs can 
work over here number one for example scrotanin   can bind here five hydroxy tryptamine that can 
bind here and that is taken from extracellularly   transported by the receptor intersectionally 
and maybe might be it is stored again   number two some drugs can bind with these 
receptors throttling re-uptake inhibitors   like fluoxetine so fluoxetine is 
working on what kind of receptors   12 pass receptors right so let&#39;s take a break 
and then we&#39;ll continue any question you have   sir we have discussed that t3 receptors are 
intra-nuclear what about a4 actually most of   the t4 harmon before it enter into cell is 
converted into t3 and t3 is the active form   so we are more concerned about d3 receptor is 
that right thank you very much class dismiss   after this in the next lecture we will be talking 
about in detail g protein coupled receptors   and then of course g protein coupled receptors 
ligand binding domain in the next lecture   especially i will define and differentiate agonist 
antagonists which are easy to easy concept and   real concept which i will explain is partial 
agonist antagonist molecules partial agonist   antagonist molecule right or drugs then i&#39;ll 
talk about transmembrane domain effector domain   actions and functions of yes of seven pass receptors then how they activate 
the g proteins what is the exact mechanism how   g proteins bind with the effector domain of 
seven pass receptors and then i will discuss   very important thing how these 
receptors can be inactivated   seven path receptors or they can be desensitized 
or re-sensitized or downregulated or upregulated   we&#39;ll talk about these concepts in coming 
lectures class dismiss thank you very much

Transcript for:G Protein Coupled Receptors

Transcript for:
G Protein Coupled Receptors