what is up dirty medicine subscribers in today's video we are going to be talking about signal transduction i know that's what you're all thinking you're like damn it i hate this topic before i get into today's video please consider clicking the join button on my channel to sign up to be a dirty medicine member when you click the join button you will pay 4.99 a month in financial support of my channel and in exchange for that financial support you'll get the awesome dirty medicine logo which will appear after your username anytime you comment anywhere on the channel publicly you'll also get access to the locked community tab section on my channel where you can vote or comment your recommendation request for the topic of my next video any financial support that you can provide is so very much appreciated but it doesn't matter if you don't donate i'm still going to make the free videos anyway so in this video we are going to be talking about a major topic in biochemistry and immunology and this is signal transduction i cannot stress enough how high guild and important this topic is for a couple reasons one clinically the second messenger system is so important it literally has its hand in everything in the human body it controls so much of biochemistry and endocrinology and neurology and neuroscience and psychiatry it's literally in every topic so clinically it's really important to understand the foundation of how all of that communication works but then as far as u.s emily or complex is concerned it's a really high yield topic i think that test writers know that medical students just cannot stand studying this they punt this they chalk this up and figure you know what if i get a question i'm just gonna take a guess and that's that but no no no no you're not gonna do that that is a defeatist attitude and here at dirty medicine i do not believe in giving up what should be free points so in this video i'm going to teach you everything that you need to know to get most if not all of your questions correct when it comes to signal transduction so let's get started by talking about g protein couple receptors so where do we begin well we've got a plasma membrane which you see here on the slide and embedded within that plasma membrane is a receptor and this is the g-protein-coupled receptor and if you look at the plasma membrane here the receptor portion has this seven transmembrane domain that kind of goes in and out in and out and it loops in and out from the intra and extracellular side now on the extracellular side you see that little cup and that's where our signal is going to bind but this is the receptor now the receptor is connected to or associated with a g protein network and that g protein network is com consists of three subunits hence the name heterotrimeric g protein it's a trimeric tri meaning three three subunits so we've got the gamma alpha and beta subunit now how this works is the signal binds to the little cup of the receptor which you see in the upper left-hand part of this slide and when that happens you get a little bit of conformational change within the trimeric protein subunits of the g protein so the gamma and the beta subunit stay up around the plasma membrane but that alpha subunit kind of dissociates a bit and i'm oversimplifying this for the purposes of explaining it it doesn't quite work like this exactly in space but on that alpha subunit you get the conversion of gdp to gtp and when the gtp is on the alpha subunit of the g protein you have a gtp bound alpha subunit that's now active now when the alpha subunit is active it can act in one of a few ways it can be g sub s or g sub i the g sub s activates adenylyl cyclase and adenylcyclase's role is to convert atp into c amp and then c amp will activate protein kinase a or pka and then pka will have further downstream secondary messenger effects so g sub s activates adenylyl cyclase which catalyzes the conversion from atp to camp and then camp goes on to activate protein kinase a so big picture here g proteins alpha gs stimulates s for stimulates adenylyl cyclase which turns on camp which turns on pka now gi i for inhibitory does the opposite it inhibits adenylyl cyclase which never allows the conversion of atp to see amp which never allows pka to be activated which never allows pka to go on and carry out its secondary messenger effects so alpha subunit of the g protein can either stimulate through gs or inhibit through gi now there's another function that the alpha subunit can have that's not gs and that's not gi and instead of working through a dental cyclase and then camp and then pka it works through a completely different system so i'm going to show that on the right hand side of this slide so to be clear we're still talking about a g protein coupled receptor where the signal binds to the receptor it induces the little bit of conformational change gdp still goes to gtp you still get activation of the alpha subunit of the g protein and this is where we start to get a little different here so instead of stimulating through gs or inhibiting through gi you're going to get stimulatory action but through gq and gq will go on to activate phospholipase c now phospholipase c will activate the conversion of pip 2 to ip3 plus dag dag and it's ip3 and dag which each carry out unique effects so ip3 causes a release of calcium from the endoplasmic reticulum and dag activates protein kinase c or pkc now the combination of calcium being released from the endoplasmic reticulum and protein kinase c being activated by dag will both have further downstream effects particularly calcium which will go on to activate a whole host of enzymes and carry out secondary messenger functions so on the right part of this slide the big picture idea is that alpha subunit of g protein works through gq which stimulates phospholipase c which stimulates pip2 into both ip3 and dag ip3 causes calcium release dag activates protein kinase c and then both calcium and pkc will go on and carry out downstream secondary messenger effects so huge picture let's pause take one big step back and look at this big picture what's happening a g protein-coupled receptor can cause either the activation of protein kinase a the inhibition of protein kinase a or the activation of both calcium and protein kinase c and depending on what the effect or the intended effect is through the secondary messenger system protein kinase a calcium and protein kinase c can go on to have further intracellular control so that's the big picture of what's going on here and now the question in your mind i can hear it right now dirty how do we remember this so here's my mnemonic again big picture g protein turns on a dental cyclase turns on camp which turns on pka so my mnemonic is that you go to ac for craps and poker so i know gambling is legal in a lot of areas now but back in the day you really had to either go to las vegas out in the west or atlantic city or ac over on the east coast so you go to ac for craps and poker g for g protein ac for adenylyl cyclase the c in craps is the c in camp and the p in poker is the p in pka so dumb mnemonic i get it but it's better than nothing now the only other thing that i need to mention about this g protein coupled receptor pathway are the types of endocrine hormones that are under the control of the various elements of this signaling pathway so when it comes to the camp pathway the endocrine hormones that are under the influence of this pathway is everything that you see on this slide so we've got fsh lh ac th tsh crh hcg adh and that's specific to the v2 receptor msh pth calcitonin ghrh glucagon and then histamine and specific to histamine we're talking about the h2 receptor so these are all of the endocrine hormones under the control of camp and then likewise we need to talk about the endocrine hormones under the control of ip3 so this is working through the other part of the g-protein coupled receptor pathway through gq phospholipase c and then ip3 so ip3 controls things that you see on this slide so gnrh oxytocin adh at the v1 receptor trh histamine this time specific to the h1 receptor angiotensin ii and gastrin so these are all under the control of ip3 now let's switch gears and talk about the next type of signal transduction pathway we're going to talk about receptor tyrosine kinases receptor tyrosine kinases are actually the largest class of signal transductors and these are very unique because receptor tyrosine kinases actually have inherent enzyme activity so yes it's a receptor but it also is technically an enzyme hence the name receptor tyrosine kinase now how does this work so growth factors or local signaling molecules will bind on top of the receptor tyrosine kinases and when this happens it kind of forces the two components or the two receptor tyrosine kinases to move close to one again to one another and link up also known as dimerization so now we have the formation of a dimer and then the dimer undergoes this really unique process known as cross phosphorylation so pretty much what's going on here is that there is the tyrosine kinase activity in each of these dimers cross phosphorylate each other so they're they're literally phosphorylating tyrosines on the other receptor tyrosine kinase and this whole process that you see here with my little white lines showing you that it's crossing is known as cross-phosphorylation now the result of this cross-phosphorylation is that you get this thing called an sh2 domain and that's basically a binding site up on the top of the receptor tyrosine kinase where various enzymes and other molecules can bind to to kick off complex signal transduction so let's take this one step further and just imagine that you've got these dimerized receptor tyrosine kinases and they're sitting there just ready to do their job so along comes this ross ras and typically ross is inactive when it has gdp bound to it but once the signaling molecule at the top of the receptor tyrosine kinase which is here shown in light blue binds you get dimerization you get cross phosphorylation ross binds to the sh2 domain and then ross can become activated so the way that that happens is that the gdp gets exchanged for the gtp and now you've got activated ras and now ras will undergo this complex pathway where it basically will go to roth which will go to mech which will go to irk and it's not important that you understand what each of these things are doing but what is important is that you understand that as you go down through this pathway you have the presence of what's known as activator and these are serine threonine kinases in the map kinase cascade and basically what's happening here is because all of these kinases are activators and control this pathway at each step of the way so as you see here map kinase kinase kinase controls raf map kinase kinase controls mech and map kinase controls erc so pretty much as you go down you just drop a kinase each time but the big picture here is that because each of these kinases phosphorylate multiple substrates as you go down that initial signal pretty much gets amplified so this leads to a very strong output at the bottom of this transduction cascade which can then go on to regulate lots of different transcription products and this will have pretty profound effects as this moves throughout the the cell so this is a very complex pathway but for the purposes of usmle or comlax really what you need to know is that it is how the receptor tyrosine kinase works back at the top so dimerization cross phosphorylation ross rough mech arc and as you go down you have activators map kinase kinase kinase and then just drop one kinase as you go down so that's kind of the big picture with a lot of nitty-gritty details woven in in between and just like we talked about with g-protein-coupled receptors it's really important to know the different endocrine products which are controlled by this pathway so just to summarize as you see on this slide receptor tyrosine kinases control insulin igf-1 fgf f and egf but dirty how the hell will i remember the pathway alright so my mnemonic here is when you think of receptor tyrosine kinase think rtk receptor tyrosine kinase rtk and rtk should remind you ross iii kinases so what does this tell you all of this is kicked off by ross and then three kinases reminds you that the next thing after ross starts with map kinase kinase kinase and then three kinases as you go down just drop a kinase so rtk receptor tyrosine kinase r for ross t for three k for kinase and then if you know that you're starting with the three kinase map after ross just drop a kinase as you go down simple done easy points so that's receptor tyrosine kinases the final signal transduction pathway that we need to talk about and honestly it's the easiest one to learn and to memorize so i saved it for last so that you can end on a high note and feel like you dominated this video is the cgmp pathway so the cgmp pathway is just pretty simple so i'm just going to fly through it so you've got nitric oxide which basically comes inside of the membrane and interacts with guanolate cyclase guanolate cyclase converts gtp into cgmp and then cgmp goes on to activate protein kinase g the reason i think that this pathway is just a little bit easier to remember and put all these things together into this one box is because pretty much everything in this pathway with the exception of nitric oxide has the letter g so guanolate has g c gmp has g protein kinase g ends with g so this is all the g's which get started by nitric oxide now the endocrine hormones that are controlled in this pathway are bnp and and e-d-r-f and just as like a big picture idea you just want to know that the cgmp pathway has really profound effects on smooth muscles so this pathway has a lot of effects on vasodilation so for usmle and comlex just know that nitric oxide kicks off all the g's so guanolate c g m p p k g and that it controls bnp and p and e d r f and that is it for this video i know it was a lot of nitty gritty information but it's all very high yield so make sure you know this information well