foreign we're going to cover the four main types of receptor proteins we'll describe each receptor's structure and function and identify key drugs that interact with these receptors in the previous lecture we introduced the concept of pharmacodynamics which is the study of how drugs interact with the body and produce their effects are simply what the drug does to the body receptors are one of the four main types of drug targets now before we break this down further why is this important why are receptors important well receptors serve as the key players in mediating the effects of drugs that can specialized proteins located on the surface of cells or within cells ready to receive signals and trigger a cellular response upon binding to specific ligands you will have come across receptors in your previous studies of Cell Biology or physiology okay now receptors play an important role in cellular communication they recognize and respond to chemical Messengers including endogenous substances like neurotransmitters hormones and cytokines and exogenous substances such as drugs and toxins and this leads to functional changes in cells organ systems and the body as a whole one process you may have heard of before is signal transduction or receptor coupling which refers to the steps that occur after a ligand binds to the receptor so once a ligand binds to a receptor it's going to initiate a series of steps within the cell and all of these different steps are what we refer to as the signal transduction pathway okay and there are different signal transduction mechanisms that exist in the body that leads to diverse functional effects and outcomes and this leads to the question of how receptors exhibit diversity in terms of structural function and response time scales so some receptors respond quickly such as those involved in fast neurotransmission as synapses other receptors like steroid hormones have slower single transduction mechanisms leading to longer time scales for observing their effects so it's going to take much longer to see the effects of a ligand activating a steroid hormone receptor So based on both their structure and their signal transduction mechanisms we can classify or group receptors into four main types we refer to these as receptor super families now the thing is not every receptor is going to fit perfectly into the Super family so just keep in mind that this is just a broad framework for understanding receptors and that there are exceptions the four main receptor types are ligand-gated ion channels G protein coupled receptors kinase linked receptors and nuclear receptors so let's now subtract complexity and break down the ligand-gated ion channels which are sometimes called ionotropic receptors so I can get iron channels consists of transmembrane proteins that form a water-filled pool these proteins span or cross the cell membrane they assemble into clusters or complexes in the plasma membrane so here we have a closed Channel and let's add in some signaling molecules and when these ligands bind to the channel it's going to create a pore that allows the movement of ions along their concentration gradients either into or out of the cell our effector here is an iron Channel and they open or closed based on different stimuli so in this case these channels are activated when a ligand or a drug binds to a site on the channel and opens or closes the channel both of these molecules must bind for the receptor to be activated okay the gating or regulation of the Channel's openness is controlled by The Binding of various ligands to specific sites on the Channel all right and many iron channels have multiple sites each capable of being influenced by different ligands thereby modulating the Channel's Behavior and because the channel is responding directly to a drug the channel itself is the drug Target which then causes the hyperpolarization or depolarization of the cell with that said ligand gated ion channels are the fastest Among The receptors super families the response time is milliseconds that's super fast that's because the ligand is directly interacting with the Ion channel which promptly influences iron floor leading to immediate effects on cell hyperpolarization or depolarization there are also no intermediate signaling setups steps which is why it's so fast so where would you find these ligand-gated iron channels in places where you need fast neurotransmission like we said before such as the synapses so with this understanding it implies that the coupling between the receptor and the iron channel is a direct one all right now different ion channels exhibit selectivity for specific ions based on the charge and size of the poor structure for example there are iron channels selected for sodium potassium calcium and other ions it's also important to note that ligand-gated ion channels often exist as multimeric complexes composed of multiple protein subunits multimeric means they're made up of multiple different protein subunits okay there are several structural families the most common being heteromeric Assemblies of four or five subunits with transmembrane helices assembled around essential aqueous pool let's take a closer look at the structure so here you can see a single protein which is one protein of a ligand-gated ION channel let's add another one there might be four or five of these individual proteins that cluster together in a complex to form the active Channel okay now why is this important why are we talking about this that is because the multimeric nature of this channel of these channels contributes to the large amount of diversity in this receptor super family think about it different compositions of subunits can result in channels that have different structural and functional properties Channel examples include nicotinic acetylcholine receptors Gaba type A receptors and glutamate receptors let's break down the nicotinic acetylcholine receptor these receptors are found in the nervous system in areas where we need fast neurotransmission such as neurons within the central nervous system as well as in the autonomic ganglia and in the skeletal muscle cells where they are part of what's activated at the neuromuscular Junction the synapse between a nerve and muscle it's activated by the neurotransmitter acetylcholine so The Binding of either acetylcholine or nicotine activates this receptor that's where these channels got their name from nicotine is one of the ligands that binds to and activates these channels all right now remember when we said that ion channels are often multi-merit channels so there are multiple different types of protein subunits the nicotinic acetylcholine receptor is a great example of that because it's made up of five different protein subunits arranged around a central pore here that will be gated open and closed and The Binding sides for acetylcholine so this right here is a pentameric channel we have a couple of alpha subunits a beta a Delta and a gamma and this right here are the alpha helices forming gate like we mentioned before different combinations of subunits will lead to not only structural differences but also differences in their ability to bind and respond to ligands and their function effects or functional effects so in different regions of the body there will be nicotinic receptors with different types of subunit characteristics all right and the arrangement of subunits forms a binding site for acetylcholine at the interface between adjacent subunits let's look at this from a different angle these subunits group around a central transmembrane port so we have Alpha Beta Delta and Gamma subunits and when acetylcholine or nicotine binds to the recepta it's going to trigger a conformational change that opens the channel we're going to get a slight change in the three-dimensional structure that flips the channel for being closed to being in an open State okay the kinked Alpha helices are going to swing out of the way to open the pore or it's going to straighten out which again will open the channel poor once it's in an open state it allows for ions to flow through the channels including positively charged sodium ions leading to the the polarization of the cell all right now there are several drugs that affect ligand-gated ion channels including the nicotinic acetylcholine receptors one example is nicotine a highly addictive substance found in tobacco it's also used for the relief of nicotine withdrawal symptoms you may have heard of nicotine patches to treat smoking withdrawals okay so what it does is it acts as an Agonist for the nicotinic acetylcholine receptors recall that drugs that bind to inactive receptors are known as Agonist drugs okay so in the brain nicotine binds to these receptors on dopath ninergic neurons okay so when nicotine binds to these receptors it activates the iron chart what happens when the iron channels open it's going to allow the influx or flow or positively charged ions into the cell particularly sodium which would then change the cell's membrane potential causing depolarization this can then have various effects including the release of neurotransmitters like dopamine which can contribute to the pleasurable sensation and addictive nature of nicotine associated with smoking okay so that's one example of ligand gain ion channels let's go through another one Gaba receptors so the neurotransmitter Gaba is an inhibitory neurotransmitter it reduces neuronal excitability so it's involved in regulating brain function anxiety and muscle relaxation and The Binding of Gaba is going to cause potassium ions to leave the cell and chloride ions to enter the cell making the inside of the cell more negative so drugs that act on Gaba receptors can have a wide range of effects on the nervous system including sedation or muscle relaxation okay an example is diazepam which is going to enhance the inhibitory effects of Gaba and is used to treat or relieve symptoms of anxiety it has sedative properties we're not going to break this down further but as we go through the pathways and how these receptors work we can begin to understand how drugs affect these targets and how we can produce the design effects okay but now move on to G protein coupled receptors or gpcrs which is which make up the largest of the full receptor super families okay we're actually going to cover gpcrs in depth in another lecture there's a lot to cover here so for now we're going to go through an overview and introduce you to gpcrs so these bad boys are similar to like and gated ion channels in that they are found on the cell surface so their cell membrane receptors as well they're formed by proteins that are transmembrane and cross the plasma membrane generally they are formed by a single polypeptide chain so this right here is a single polypeptide chain and that polypeptide chain falls back on itself to cross the membrane seven times in total so it has seven transmembrane Alpha helices with an extracellular and terminal domain of varying length and an intracellular C terminal domain right here so the c-terminus or intracellular domain contains the binding site for G proteins whereas the ligand binding domain for these gpcrs is on the outside of the cell or deep in the clef between the alpha helical segments within the membrane all right gpcs are divided into three main classes we have three we have a a b and c so these classes they still share the same seven transmembrane Helix structure but they differ in other areas such as the length of the extracellular and Terminus and the location of The Agonist binding domain and where the ligand bonds is dependent on the type of gpcs so for gpcrs that respond to small molecules such as neurotransmitters like acetylcholine the ligand binding domain is located within the middle of these helical segments that's because in order for a molecular structure to bind to The Binding site it must be small enough to access it okay so if the ligam that activates the receptor is a peptide hormone you're more likely to find The Binding domain in the extracellular regions located outside the cell wall so the site of the ligand binding domain can vary depending on the gpcr and going back to the site for G proteins these proteins are an important part of the signal transduction mechanisms for these receptors okay let's go through an overview of what happens like I mentioned before we'll break this down further in another lecture okay let's slow down essentially when a drug comes in and binds to and activates this particular ligand binding site it will induce a conformational change in the receptor structure that changes it into an activated conformation okay when a GPC is activated this is going to trigger a conformational change in the receptor and it's going to create a high Affinity binding site for the G protein it's going to open up a region on the intracellular side of the receptor into which the G protein can bind now G proteins these bad boys here are anchored to the inside of the membrane through attached lipid residues okay their name g proteins because of their interaction with the iguanine nucleotides GTP and GDP so G proteins consists of three subunits we have alpha beta and gamma now this Alpha subunit contains the binding site for GTP and GDP whilst the beta and gamma subunits remain together as a complex and in the resting state the G protein exists as a trima which may or may not be pre-coupled to the receptor with GDP right here bound to the alpha subunit so now the gpco is activated and the g protein is also activated it combine to the intracellular side of the receptor okay and this interaction here between the activated gpcr and G protein causes the GDP to dissociate from the alpha subunit it's going to let go see you later mate and the GDP is replaced by GTP hello GTP right here and now the alpha subunit changes from the inactive GDP bound form into the active GTP bound form okay all right now that we have GTP the G protein complex will dissociate into an alpha GTP complex and a beta gamma complex so think beta gamma by complex bye bye it's saying bye to the alpha subunit so now the alpha GTP complex is the active form of the G protein and it's going to dissociate from the gpcr see you later and it's free it's now free to interact with its Target protein which may be an enzyme such as Aden allele cyclase and the beta gamma complex can do the same thing you can also interact with an effective protein which may be an iron Channel or a kinase all right we'll expand on this in the gpcl lecture but once the gpcr and G protein is activated it's going to trigger the activation of intracellular signaling pathways through interaction with G proteins so the purpose of these G proteins is that they are basically cellulite intermediaries okay they carry information between the gpcr itself and the second messenger system what are the second messenger system the second messenger system is what actually transmits information further within the cell all right the key thing here is that the G protein is a mediator between the receptor itself and some sort of Target enzyme mechanisms okay I promise you we'll expand more on this in another lecture but going back to this Alpha subunit the gtpi's activity of the alpha subunit is increased when the target protein is bound which leads to the hydrolysis of the bound GTP to GDP remember that when GDP is bound it's an interesting state so the subunits will come together again they'll have a reunion now that GDP is back in the family essentially different gpcrs couple to different G proteins which then produce different cellular responses all right let's look at a specific example of activating a gpcr the beta 1 adrenergic receptor which is found in cardiomyocytes or heart muscle cells one of the main ligands that activates this receptor is adrenaline or epinephrine when the ligand binds to the beta1 adrenergic receptor which is a g protein couple receptor it induces a conformational change that then activates the receptor which then leads to the activation of a g protein the activation of that g protein then increases the production of a particular second messenger in the cell called cyclic amp what the cyclic amp does is act as a messenger between the gpcr and a cellular Target if you've studied metabolism or seen the metabolism lecture you've seen this cutie which activates protein kinase and is involved in the regulation of glycogen synthesis and breakdown but in this case in cardiac muscle cells the cellular targets for the cyclic amp is the voltage-gated calcium channels that are present in cardiac muscle cells so the increased cyclic amp levels act as a second messenger and activate protein kinase a which is a protein kinase enzyme and this activated PKA phosphorylates specific Target proteins within the cardiomyocyte including ion channels so the phosphorylation of ion channels leads to increased calcium influx into the cardiomyocyte through voltage-gated calcium channels okay so again the increase in cyclic amp triggers an increase in the activity of these voltage-gated calcium channels and makes these channels open more frequently and stay open for longer so more calcium is going to enter the cell which increases the level of calcium in the cytosol all right and as you know from physiology when you have an increase in calcium levels within the cell in particular within a muscle cell that leads to an increase in muscle contraction okay our end result here is that we end up with an increase in the force of cardiac contraction so elevated intracellular calcium levels enhance the contractility of the cardiomyocyte increasing the strength of each heartbeat so the heart is Contracting more forcefully and pumping more blood out every time it contracts okay so this action of the beta 1 adrenergic receptors is what is responsible for the ability of adrenaline to increase the rate and force of cardiac contraction which is something really important in the fight or flight response that you see with the activation of the sympathetic nervous system that's gpcrs let's now move on to kinase-linked receptors this is the most diverse of the receptor families so there's quite a lot of variability in terms of the type of ligand that activates these receptors as well as the type of signaling Pathways that are activated as well they're activated by hormones such as insulin and leptin they're also activated by growth factors and cytokines and they are involved in controlling solid Vision growth differentiation inflammation immune responses and tissue repair now most of these are large proteins consisting of a single chain of up to 1000 residues and they are also self-surface receptors they are membrane bound these receptors are transmembrane proteins composed of three primary domains an extracellular ligand binding domain a transmembrane domain and an intracellular kinase domain so the extracellular ligand binding domain is responsible for ligand recognition and binding so where the ligand will bind these receptors are on the cell surface so they're responding to signals from outside the cell this domain also varies in size and structure allowing for specificity in ligand recognition now the extracellular domain is connected to the inside domain of the cell via the transmembrane Helix so the transmembrane domain spans the cell membrane anchoring the receptor in place and then the intracellular kinase domain is the catalytic region responsible for phosphorylating Target proteins recall that kinases are enzymes that phosphorylate a protein they add a phosphate group and they often act as an on or off switch okay for whatever they are targeting and phosphorylating okay so quick revision phosphorylation is done by kinases and dephosphorylation removing the phosphate is done by phosphatases so as the thing implies kinase linked when these receptors are activated it leads to the activation of kinase Pathways within the cell okay there are three main types we have the receptor tyrosine kinases which includes a tyrosine kinase component in the intracellular region this type includes receptors for many growth factors such as epidermal growth factor it also includes the insulin receptor there's also the receptor serine threonine kinases which has a similar structure to rtks but instead of phosphorylating tyrosine residues they phosphorylate serine and or threonine residues an example is the receptor for transforming growth factor okay and then we have cytokine receptors these ones lack intrinsic enzyme activity so when a lie again is bound they activate a various tyrosine kinases such as the Janus kinase or Jack cytokines such as interference and Colony stimulating factors that promote cell growth and differentiation as well as immune responses are the ligands for these receptors now earlier we mentioned that kinases are enzymes that phosphorylate proteins and that is because the process of protein phosphorylation is important in controlling the function of proteins such as enzymes receptors ion channels and transport proteins that are involved in regulating cellular processes in certain cases the activation of kinase activity is an inherent property of the receptor itself so when the receptor is activated the intracellular domain of the receptor forms an activated protein kinase and this activated kinase can then phosphorylate other Target proteins initiating Downstream signaling events all right in other instances the activation of kinase activity is more indirect so the intracellular domain of the receptor requires the assistance of adapter proteins to connect and activate the intracellular kinases these adapter proteins act as intermediaries facilitating the interaction between the receptors intracellular domain and the kinases and through this interaction the kinases are recruited and activated leading to subsequent phosphorylation events and initiation of Downstream signaling Pathways so signaling through these kinase link receptors is much slower compared to our previous two types of receptor families okay let's focus on the epidermal growth factor receptor which is involved in many important events including proliferation and migration so this receptor belongs to a class of receptors called recepta tyrosine kinases which are widely present in the body and serve as important drug targets the name receptor tyrosine kinase reflects the receptor's response to extracellular signals and its ability to phosphorylate tyrosine residues through its kinase activity which is where the term tyrosine comes from okay so in this case as its name implies the egfr responds to epidermal growth factor EGF and is the ligand that binds to and activates these particular receptors this is an example where the receptor has its own kinase domain okay we can break this pathway down into a series of stages ligand binding receptor dimerization receptor orophosphorylation and the recruitment of signaling proteins which leads to the activation of further signaling Cascades okay so this right here is the egfr ligand so this is the epidermal growth factor itself finding two molecules of the egfr protein as the ligam binds it's going to bring these two molecules together and causes cross-linking between the two proteins this biting event causes two egfr protein molecules to come together and form a dimer which triggers the activation of the intracellular kinase domain located within the receptor once it's activated the kinase domain phosphorylase specific tyrosine residues initiating a Cascade of signaling events okay so ultimately the main thing that's occurring Downstream of this egfr activation are changes in cellular function that relate to cell migration cellular growth and cellular proliferation now in normal physiology the egfr plays an important role in the development of some organs and this regulation of egfr activity is associated with different types of cancer there are a number of cancers that are associated with over activity of this egfr and the over and that over activity then leads to excessive cell growth and proliferation leading to tumor formation okay so now in the context of drug targets there are different approaches to targeting egfr for the treatment of certain cancers such as colon cancer breast cancer and certain types of lung cancer anti-cancer drugs May prevent ligand binding to inhibit receptor activation or Target the intracellular kinase domain so understanding the intricacies of egfr and its significance in both normal physiology and disease States provides valuable insights into the development of targeted therapies aimed at modulating EG of our activity in cancer treatment okay so that's kinase linked receptors let's now move on to our final type of recipe family which are the nuclear receptors okay unlike the other three receptors which are predominantly found on the cellular membrane nuclear receptors are primarily located inside the cell however despite their name nuclear receptors are not all located within the nucleus instead many of them reside in the cytosol until a ligand binds and activates the receptor and then they move into the nucleus they are also known as ligand activated transcription factors which have the ability to affect Gene transcription and bind directly with DNA they have a role in regulating metabolic and developmental processes because they have the ability to influence the transcription and expression of several genes and proteins now we can classify nuclear receptors into four classes class one the steroid receptors examples include glucocorticoid mineral or corticoid progesterone and estrogen class II examples include thyroid hormone and retinoic acid class 3 the homo domeric often receptors and class 4 monomeric orphan receptors okay now in terms of the structure all nuclear receptors are monomeric proteins typically composed of several domains each with distinct functions let's go through this so they all contain a variable n-terminal domain a DNA binding domain a hinge region and a conserved ligand binding domain and a variable C terminal domain the n-terminal domain contains the activation function 1 which interacts with co-regulatory proteins it binds to other cell-specific transcription factors and has the ability to change The Binding of the receptor itself possesses a binding domain where the ligand can interact with it okay so it wants to lie again bunch the receptor the ligand receptor complex moves into the nucleus and directly interacts with the DNA through a DNA binding domain the DNA binding domain allows the receptor to bind to specific hormone response elements in the DNA sequence okay and then we have the hinge region which connects the dbd to the ligand binding domain this is the part that allows the molecule to dimerize to combine with other nuclear receptors it also contains the activation function 1 and contributes to the dimerization interface and finally we have the C terminal domain which contains the ligand binding domain and is specific to each class of receptor this region is responsible for ligand binding and contains activation function 2 which interacts with curl regulatory proteins now when it comes to ligand binding nuclear receptors combine a wide range of ligands including hormones vitamins and synthetic compounds and this binding induces conformational changes that enable the receptor to interact with co-regulatory proteins okay so ligands can either activate or inhibit The receptors transcriptional activity now the effect on Gene transcription depends on the specific ligand and receptor as well as whether the ligand receptor complex binds to response elements in the promoter region that activates or suppresses Gene transcription okay now one of the most relevant types of nuclear receptors are those that bind to steroid hormones class one steroid hormones which are lipophilic due to their cholesterol back burn can easily cross the cell membrane since nuclear receptors are located within the cell lipophilic ligands can readily interact with their target nuclear receptors once they enter the cell now due to their role in altering Gene transcription and protein synthesis the functional effects of nuclear receptors are relatively slow to Manifest this is because protein synthesis is a time-consuming process okay let's go through a specific example the mineral corticoid receptors so these receptors are present in various cells and tissues with their most crucial role being in the kidneys particularly in the latter part of the Nephron so these receptors are found in the cytosol and in this case we'll focus on the aldosterone receptor as aldosterone acts as a ligand that activates this receptor where it moves into the nucleus aldosterone is a steroid homer so you can freely diffuse from the bloodstream across the cell membrane of the epithelial cell interacting with a specific receptor once the aldosterone mineral corticoid complex enters the nucleus it plays a it plays a role in regulating Gene transcription specifically enhancing the expression of transport proteins so these transport proteins include ion channels and carrier proteins or pumps that facilitate the reabsorption of sodium in the kidney assuming recall from physiology sodium is initially filtered in the kidney but is then reabsorbed back into the bloodstream aldosterone increases and upregulates the activity of these iron trials and pumps leading to the reabsorption of sodium from the urine or filtrate back into the bloodstream so over time this results in increased sodium retention within the body but the thing is too much aldosterone can cause high blood pressure because aldosterone makes your kidneys hold on to sodium and mortar which raises your blood pressure but there are drugs that block the effects of aldosterone these are called aldosterone receptor antagonists sometimes called MREs so mras such as spironolactone block the effects of aldosterone and is used for the treatment of hypertension so what it does it competitively inhibits The receptors in the distal tubule to promote sodium and water excretion and potassium retention okay so your kidneys are able to release excess salt and water from your blood so there is a nuclear receptors before we end the slack child let's bring everything together and summarize the four main types of receptor protein super families because we covered a lot so starting with the LIE again ion channels which are ion channels embedded in the cell membrane they are activated when a specific ligand binds to them causing a change in the gating of the channel this alteration allows ions to enter or exit the cell resulting in the change in the cell's polarity this rapid response occurs within milliseconds so they are the fastest on the time scale of responses moving on we have G protein coupled receptors gpcrs these receptors are also located in the cell membrane and are activated by ligand mining upon ligand binding intracellular signaling Pathways involving G proteins are triggered gpcrs mediate a wide range of effects which we'll discuss later in another lecture okay so compared to ligand geared ion channels the response of gpcrs is slightly slower typically taking seconds to respond to ligand binding next we have kinase link receptors predominantly found on the cell membrane when a ligand activates these receptors a series of intracellular events occur involving the activation of various protein kinase Cascades so these protein kinases can lead to a diverse cellular effects often through the mediation of Gene transcription or protein synthesis and on the time scale it can take hours and finally we have nuclear receptors which differ from the other receptor types as they are primarily located inside the cell of in the cytosol so when a ligand buys to these receptors they translocate into the nucleus where they regulate Gene transcription ultimately influencing protein synthesis unlike the previous receptor types nuclear receptors act more slowly taking hours to days to exert their effects after like an activation now it's important to note that each receptor super family has its unique characteristics response times and mechanism of action understanding these receptor types is essential for comprehending the diverse ways in which cells and organisms respond to different ligands and drugs thank you for watching this video make sure you subscribe to EKG science so you don't miss a single lecture and remember subtract complexity and slow down to study the next lecture simply click the next video or you can view the entire playlist