1-8-7.Drug Action.txt

7/29/2019 1-8-7.Drug Action.txt

1/15

Hello. Today, we are going to move on topart two of fundamentals of pharmacology,pharmacodynamics. We have spent lastcouple of sections discussing all thepharmacokinetics principles. In otherwords, what the body, body does to thedrug. In the next couple of sections, wewill do the reverse. Pharmacodynamicsdescribes the body's response to a givendrug. And in terms of clinical practicethis is the piece that we have greatestinterest in. So section five,pharmacodynamics, introduction to drugaction. So, we're going to return at thebeginning of this section to a slide thatI have shown you previously. In the palerbackground in the top half of thisparticular slide refers to the PK profile.We are now going to discusspharmacodynamics. This is the effect thatone expects to see or maybe doesn't wantto see i.e. Toxicity in terms ofpharmacologic effect. We differentiate

between pharmacologic effect and clinicalresponse. Pharmacological effect is theimpact of the drug at both the intendedand unintended sight of action. Typicallyhere, we talk about receptor activity. Theclinical response is the sort of responsethat you as the consumer or me as theprescriber might expect to see in responseto drug delivery. For example, giving apatient a drug to lower blood pressure.The clinical response would be the bloodpressure lowering response. Thepharmacological effect would be the

mechanism of action of the drug. How didthe drug lower the blood pressure? And youwill see the bottom of this slide of theleft hand side, that we talked aboutefficacy, the intended effect andtoxicity, the unintended effect. So whenwe talk about pharmacodynamics, receptorbiology is a cornerstone to our ability tounderstand drug action. So we will followin this particular section. A introductoryto the concept of receptor activation. Asubsequent class will talk about the doseresponse in, in response to receptor

activation. So the learning objectives forsection five and six include thefollowing. Understand the principle ofdrug receptor interactions. Appreciate howreceptors determine drug response. Be ableat the end of these two classes to definefive types of receptors. Know what theylook like, know how they work, know howtheir function can be modulated. Inaddition in the sections, we will spend a


2/15

lot of time talking about G proteincoupled receptors. One of the five type ofreceptors that I'm going to introduce.Because G protein couple receptors formthe cornerstone of receptor biology anddrug action, we're going to dive intogreater detail, about this particular typeof receptor. So at the end of this, I'dlike you to know the structure of a Gprotein-coupled receptor and the basicsequence of events following an agonistbinding to the receptor. I'd ask you toknow the three classes of G proteins andthe effectors that they regulate. I'd likeyou to appreciate how G protein coupledreceptor subtypes provide the opportunityof therapeutic leverage. And I want you tolearn how receptor activity is modulated.A lot of these terms will be foreign toyou. I will introduce them and do my bestto explain them to the point where youwill be able to understand this material.This materials is going to be a bit morecomplex than that what we have taught

before. It may require some backgroundreading in addition to what I providehere. I will try to explain theseprinciples as thoroughly as I can. Solet's start off with the rudimentaryaspects of pharmacodynamic principles.First of all most drugs bind to a receptorto bring about an effect. The types ofactions that we see commonly in humanbiology and pharmacology are detailed her.The drug, in parenthesis D plus thereceptor, effector, referred to as R bindtogether to give you a complex denoted

here, drug receptor complex. Followingcreation of this complex there is a neteffect produced referred to as thepharmacodynamic effect. Another, examplewould be a drug and a receptor again,create a drug receptor complex whichelicits an effector response or thecreation of an eff ector molecule. And itis this molecule that brings about theultimate pharmical dynamic effect. Thethird example, is the first two steps areexactly the same as the previous example,create the drug receptor complex. And that

at this complex that induces theactivation of a coupling molecule to bringabout an effector molecule to bring aboutan effect. So, as you can see from thesefirst three examples, we have increasinglevels of complexity, of different steps,that undergone, in order to bring aboutthe pharmacodynamic effects. It is thiscomplexity of drug receptor interactionthat makes pharmacology sometimes


3/15

challenging to understand when areevaluating drug responses. The lastexample, is a common example in humanbiology whereby inhibition of metabolismof an endogenous activator. This issomething that exists in each of us, inhumans referred to as endogenous,naturally occurring activator. As a resultof decreased break down of the natural orendogenous activator, there is increasedactivator action on the effector molecule,resulting in an increased effect. You canthink of an analogy here being just anincrease concentration of the endogenousactivator. Think about insulin. Thinkabout asetilkoline. These are naturallyoccurring hormones and neuro transmittersthat exist in the body. Under normalcircumstances, they are broken down. Anydrug that results in the naturalinhibition of the break down of theendogenously synthesize compound willresult in increased duration ofpharmacodynamic affect. So these are four

rudimentary examples of how drugsinterfacing with receptors bring abouttheir individual responses. What is areceptor? Well, the simplest definition isthe following, a receptor is a proteinthat binds a signaling molecule, wetypically in the drug world refer to thisas an agonist, and in doing so, generatesa signal of its own. Let me repeat that. Areceptor is a protein that binds asignaling molecule and in doing so,generates a signal of its own. Think ofdominoes as your analogy. Let's say we

have a stack of dominoes lined up on aflat surface. You tip over the firstdomino. Your tip, your finger is theagonist. It touches the first domino.Consider that to be your receptor. Itcauses the falling down of subsequentdominoes. These are the signals that aregenerated as a result of receptoractivation. Receptors themselves arethought to exist in an inactive and anactivated form. The inactive form isdesignated r subcase lowercase i. Theactivated form of the receptor is r

subscript a. Some receptors remain in anactive conformation even in the absence ofan agonist binding. This is an importantconcept. It is referred to as constitutiveactivity. In other words, there exists thephenomenon whereby a receptor can beactivated in and of its own right. Anagonist is a molecule that binds to andactivates a receptor to bring about aneffect. I'm going to repeat that because


4/15

it's a very important definition. Anagonist is a molecule that binds to andactivates a receptor to bring about it'seffect. If a drug, given in sufficientquantity to saturate the receptor pool,binds to the activated form of thereceptor and stabilizes it so that a largepercentage of the receptor stays in theactivated form. It is called a fullagonist. In other words the majority ofthe receptors that are the natural ligandfor that agonist are in the activatedform. They are kept in the activated formby the agonist binding to the receptor.This is called a full agonist. Let me showyou a picture. I'll ask you to concentrateon the top part of this particulardiagram. In the top left corner depictsyour inactivated or your inactor form ofyour receptor. On the bottom part of theleft hand diagram is a inactive form ofthe receptor with your drug bound to it.On the top right hand corner is theactivated receptor with the drug in

equilibrium and the drug binding to thereceptor to bring about the activated formof the receptor bound to the drug. You cansee here, that if you have a drug thatbinds to a receptor, you bring about alarge affect. Now what about if you have adrug that binds to the activated form andstabilizes it. So that a smallerpercentage of the activated receptor poolis, unaltered no matter what dose of thedrug is given. It's called a partialagonist and the reason for this is, isthat not all of the receptors are

maintained in the bound form in anactivated state. So if we go back to ourpicture, here we see a drug in itsactivated form partially bound giving asmaller effect. A third concept that I'dlike to, you to appreciate is an inverseagonist. If a drug has a higher affinityfor the inactive form of the receptor andstabilizes a large fraction of theinactive form of the receptor pool. Thenthe constituative activity that we talkedabout previously will be lost. So, let'ssay for example we have a receptor, for

asetilkolin. Asetilkolin is aneurotransmitter. It is responsible inpart for muscle tone. It is one of theneurotransmitters that allows us to standfor long periods of time through it'sability to maintain muscle tone. If we usea drug that prevents the activation of thereceptor to convert it from the IRI forminto the RA form, then we lose some ofthat constitutive activity. This is called


5/15

an inverse agonist. It's inverse becauseit removes some of the natural inherentproperty of the receptor, the constitutiveactivity but it's called an agonist,because it's still binding to thereceptor. And then lastly is the conceptof an antagonist. This is a molecule thatprevents activation of the receptor by anagonist. It's different from an inverseagonist for many reasons. One, it binds tothe different site than the active site ofthe receptor. Two, it blocks the bindingof the natural agonist to the active formof the receptor, conceptually speaking,like covering an with an envelope. Solet's look at our picture again. Down herewe see. On the y-axis, the response to adrug. On the x axis is incremental doses.These are shown as log dose responsecurves because they're easier to interpret. Than regular dose response curves. Sothis particular curve here represents afull agonist. A dose response curvefollowing administration of a full

agonist. So remember what we said before.The full agonist binds to the activereceptor to create a activated receptordrug complex, bringing about a potentialof a maximal effect. This is the fullagonist dose response curve. Thisparticular curve here refers or, orrepresents a partial agonist. Here we seethat the, the drug does indeed bind to theactivated form of the receptor but nomatter how much drug you give shown herealong the x axis of increasingconcentration or increasing dose of the

drug. The dose response curve plateausout. You cannot induce a further increasein agonist action. This is referred to asa partial agonist. An antagonist as wesaid before, prevents the binding of thenatural agonist. So, this is the flat lineso the drug response curve represents noactivity. And then finally is the inverseagonist and remembering that the inverseagonist binds to the drug in the inactiveform of the receptor, I'm sorry binds tothe receptor in the inactive form of thereceptor. And eliminates the constitute

activity that, that receptor wouldnormally demonstrate. So this representsthe inverse agonist dose response curve.This appreciation of inactive versusactive receptor forms is important inorder for you to be able to understand thedifference between agonist effect,antagonist effect and inverse agonisteffect. Now the picture gets a little bitcomplicated as follows. At the top of this


6/15

slide you see what we've talked aboutbefore, drug, receptor, effect. Nodifferent than what we talked aboutpreviously. Shown in the top of the slidepanel A is representative of an agonistbinding to the active site of the receptorand activating the receptor to bring abouta clinical, a pharmacodynamic plus orminus a chemical response. And that inthose response carves shown here on theright, is represented here. In addition tothis, we have the ability t o modulate theresponse of the agonist, to diminish it.This is referred to as a competitiveinhibitor. Something that will reduce themaximal response to the natural agonist.And this is referred to in this particularcurve here. Finally, we also have theopportunity to incorporate what are calledallosteric modulators. These can beactivators or inhibitors. In example C,shows the ability of a molecule to bind toa site on the receptor. That is not theactive site where the agonist binds, but

by binding of the alosteric activator itenhances the response to the naturalagonist. So you have the agonist bindingto the receptor, activating it and thenyou have the alosteric molecule thatenhances the response to the agonist. Thisis shown by this particular curve here.And what this curve demonstrate is, isthat you get a much more amplifiedresponse at a lower dose of the agonistwhen it isn't present, when it is presentwith the alosteric activator. And thenfinally, is the concept of the opposite

approach in allosteric inhibitor. Again,this is a molecule that binds to thereceptor. A site that is distinct fromwhere the agonist binds but by binding the[inaudible] inhibitor, it diminishes theresponse to the natural agonist, and thatis shown, by this particular responsehere. In these dose response curvesanything that shifts the curve to the leftenhances the overall activity of the drug.Things that shift the curve to the rightreduce the activity of the drug or theagonist. So these concepts of agonist,

partial agonist, inverse agonist,antagonist, competitive inhibitor,allosteric activator, allostericinhibitor, are all common concepts thatallow us to develop drugs, evaluate drugs,and appreciate their potential impact inclinical medicine. One example where weare seeing a huge explosion in the arenaof cancer chemotherapy is the conceptallosteric activators that we are able to


7/15

use small molecules to amplify theresponse of other chemotherapeutic drugs.In such a way, that it permits us to uselower doses of the agonist. Therebypossibly avoiding toxicity associated withhigher doses of the agonist because we'reable to maximally activate the response tothe receptor. So, allosteric activators isa common approach in trying to amplifyefficacy. And reduce toxicity which isincredibly important in cancerchemotherapy. So in this particularsection we are going to talk aboutreceptor activation and a lot of what I'mgoing to talk about has relevance tonormal physiology and human biology. Butmy emphasis is going to center on drugreceptor interactions. In order toappreciate this part of thepharmacodynamics section, I want toexplain to you some important generalconcepts. Cells contain a large array ofreceptors for naturally occurringsubstances such as hormones, insulin,

thyroxin, cortisol. Neurotransmitters suchas acetylcholine, adrenaline,noradrenaline, or sensory inputs, light,noise, taste, smell. Receptors areactivated by an array of endogenouscompounds, examples that I just gave you.More than a thousand different receptorshave been identified in the human genome.This is a very large concept toappreciate. The vast majority of all thethat drugs we use in clinical medicinetoday operate through receptors. Thisincludes receptors on enzymes, receptors

on cell membranes, receptors within cells,etc. Receptors importantly mediate theactions of both pharmacological agonistand antagonist. Sectors largely determinethe quantative relationship between doseor concentration of the drug and thepharmacologic effect. This is referred toas the dose-response relationship. We willreturn to this concept in the next sectionin this course. The concept ofquantitative dose response is criticallyimportant in drug evaluation. Both in thedevelop, the development stage of novel

therapeutics but also in the practice ofmedicine in prescribing and estimatingmagnitude of response both effective andtoxic. Receptors very, very importantly,are responsible for the cell activity ofdrug action and this I will s pend a gooddeal of time talking about. For most drugswithout the knowledge of receptors towhich they bind, it is very difficult tounderstand the mechanism of action of the


8/15

drug, the selectivity of the drug, or thelack their of and to appreciate the trueintricacies of the dose responserelationship. Having said that, there aremany drugs that we use in clinicalmedicine today that have been around formany, many decades in clinical practice.For which we don't know the receptor butin this era, our development of drugsformally involves an evaluation ofmechanism of drug action. In an honestattempt to a try, to try to appreciate thereceptor that mediates the response of anynovel therapeutic that will come tomarket. Most receptors are proteins andthus they abide by all of the propertiesthat are detailed for proteins in terms ofsynthesis, biotransformation, metabolism,etcetera. The best characterized drugreceptors are regulatory proteins. Theymediate the actions of endogenous chemicalsignals such as neurotransmitters andhormones as I've described previously.Other drug receptors include enzymes,

transport proteins and structuralproteins. So the concept of receptorbiology is diverse. It affects everyphysiologic process in the body but forour purposes, we are going to talk aboutit in relation to drug action. Andspecifically, this next section is goingto focus on signalling mechanisms andtheir interplay in bringing aboutpharmacodynamic drug effects. So this isan overview of agonist action. And I'mgoing to confine many of my comments hereto the effect of agonists. Both naturally

occurring, and exaggeratedly administeredin the form of drug therapy. So on theleft hand side of this slide is a list ofdifferent types of agonists. First group,circulating hormones. Insulin, thyroxine,growth hormone, etcetera. The second,neurotransmitters. Adrenaline,noradrenaline, asetilkolin, serotonin,gabba, dopamine. Sensory stimulii as I'vedescribed previously. Light, taste, noise,smell. Autocrine a nd paracrine factors.These are small molecules that aresynthesized within a cell and activate

receptors on their own cells, these areautocrine or activate neighboring cells,paracrine. Paracrine, an example would beprostaglandins, small proteins that bringabout a myriad of effect. Cytokines can beexamples of autocrine and paracrinefactors that function as agonists. Andthen finally, the focus of today'sdiscussion, therapeutic agents.Therapeutic agents for the most part can


9/15

be synthesized to mirror endogenouslysynthesized compounds. For example, wegive insulin to patients with type onediabetes. The insulin that we givepatients is synthesized based on ourknowledge the naturally occurring hormone.Adrenalin, we give this to patients also.And it is synthesized based on ourknowledge of the naturally occurring neurotransmitter adrenalin also referred to asepinephrine. And then we have therapeuticagents that are completely syntheticagonist that have no resemblance tonaturally occurring endogenous compound.So, these are, this is our array ofagonist. They bind, as shown here, eitheron the cell membrane to a receptor. Theycan also cross into the cytoplasm and bindinto an intra-cellular receptor shownhere. There then ensues what is referredto as a proximal intracellular effect. Andthis is the involvement of a whole seriesof what are referred to as secondmessengers. The synthesis of the second

messengers causes a cascade of thesynthesis of a series of enzymes thatultimately will result in apharmacodynamic effect. In addition, youcan see down here the concept of therecruitment of adapters. Which mayfunction as an allosteric activator,inhibitor or just as an amplifier or areducer of the proximal intra-cellulareffect. So agonist binding to receptorbringing about a series of secondmessenger signaling pathways. Excuse me.So what are these receptors? Well there

are essentially five distinct types ofreceptors in signalling mechanismsinvolved in agonist and responserelationships. The fi rst of these, alipid soluble chemical signal crosses theplasma membrane and acts on anintracellular receptor. Two and threeinvolve a signal binding to the extracellular domain of a receptor causing anintracellular activation of signalingpathways. Number four, it's where thesignal binds and directly regulates achannel, on the surface of a cell

membrane. And then finally a signal bindsto cell surface receptor, which is aG-couple protein. We are going to delve ineach of these and give you examples fromhuman biology. This is a picture of thefive different signaling pathways. Thefirst example showing you theintracellular receptor. The second and thethird example showing you theextracellular domains with the agonist


10/15

binding, bringing about intracellularsecond messenger signaling pathways, thethird showing you an ion channel thatactually sits across the membrane of thecell and regulates the passage of ions.And then the final example, G proteincoupled receptors where you have anextracellular domain and an intracellulardomain linked to a G protein. So first ofall starting out with the first example.And remembering what we said before, thefirst example is a lipid soluble chemicalsignal, crosses the plasma membrane, actson a intracellular receptor to bring aboutits effect. The best example of this iscorticosteriods, cortisol. So, let me walkyou through this schema. This representsthe cell, everything inside. Thisrepresents the cell membrane. Outside ofthe cell is circulating plasma. So hereyou see the agonist, steroid,corticosteroid in this example, beingdelivered to the cell membrane. Just tobring you back to pharmacodynamic section

of this course, it is bound to plasmaprotein. In this particular example, it'scorticosteroid binding globulin. This isthe plasma protein that specificallycarries corticosteroids to the cell'ssurface in order to mediate itspharmacodynamic effect. So the steroid isdelivered to the cell membrane. It crossesthrough the plasma membrane. It is lipid soluble. It enters into the cytoplasm. Whenit enters into the cytoplasm it seeks outthe corticosteroid receptor. Heredesignated as R. Now in the natural

inactivated form of the receptor as wereferred to previously, there is nosteroid bound to the receptor. However thereceptor is kept in what is referred to asa ligan friendly state. It is kept in thisconfirmation by heat shock proteins. Theseare small molecules that exist commonlywithin cells. Upon exposure to thesteroid, which has just entered into thecytoplasm, the receptor becomes activated.The steroid binds to it and binding to thereceptor, activates the receptor and thereceptor loses the heat shock proteins as

shown in this part of the diagram. So younow have your steroid bound to yourreceptor. Your steroid receptor complex.Or your drug receptor complex. This has noeffect in the cytoplasm. It has to crossthrough the nuclear membrane shown here.The steroid receptor complex enters intothe nucleus. And it seeks out a particularpart of the DNA strand called theglucocorticoid response element, GRE. Once


11/15

this steroid bound receptor binds toglucocorticoid response element in thetarget chain, there is a turning on orturning off of transcription. It eitherincreases the synthesis of proteins ordecreases the synthesis of proteins,depending on the cell and the particularnecessary response. This is an example ofintracellular receptors for soluble, forlipid soluble ligans, steroid,glucocorticoid steroid hormone receptors.The odd set of action. Typically takesabout 30 minutes to several hours. So whatwe are seeing here is the processinginvolving multiple different steps.Ultimately resulting. In an altering andthe synthesis of proteins. The duration ofresponse can last for several days becauseof the relative slow turnover of enzymesand proteins. So once you turn on thesereceptors, it is expected that thepharmacodynamic effect of turn on thereceptor is going to have a reasonablylong duration of action. We use this

information cli nically. It is veryimportant how we use this informationclinically and this is an aspect that youwould learn in future courses. The secondreceptor that we're going to discuss iswhere the signal, the agonist binds to anextra cellular domain of the receptor.Activating the enzymatic activity of thecytoplasmic domain of the receptor. So theexample that we're going to use here ofthe cytokine receptors. So the structureof the cytokine receptors, I'll show youpicture in a moment, is such that they

have an extracellular and an intracellulardomain. They span the cell membrane. Theintersaliar domains, of these receptors,exist as monomers. However, when theagonist binds to the extracellular domain,they dimorize, they come together, to formcouplets. So, the signal binds to theextracellular domain of the receptor,activating the enzymatic activity of thecytoplasmic domain, via dimorization.These receptors cannot be activated in sofar as we know, without dimorization. Oncedimerization occurs. Separate mobile

protein tyrosine kinase molecules,referred to as JACK, are activatedresulting in a series of phosphorilationof signal transducers and activation oftranscription molecules referred to asstack molecules. Again here, much likeintracellular receptor pathway, we seemultiple steps that result, that arenecessary to result in a pharmacodynamiceffect. The step molecules ultimately


12/15

travel to the nucleus where they regulatetranscription. So, unlike the previousexample where the, the ligand boundreceptor travels to the nucleus, here itis the product of the activation of thereceptor on the cell membrane that, thatis transmitted into the nucleus toactivate transcription. Common ligands inhuman biology for cytokine receptorsinclude growth hormone, erythropoietin,this is a hormone that regulates thesynthesis of red blood cells. Interferon,also a naturally occurring cytokine thatis a regulatory component in controllinginflammatory processes. So let's look at apicture to try and explain this a littlebit better. This is your cell membrane.Here you can see the extracellular domain,and the intracellular domain. In theinactive state, these receptors exist asmonomers. Along comes a cytokine molecule.Remember cytokines from inflammation, theycontribute to normal inflammatory and alsoderranged inflammatory responses. When the

cytokine molecule binds to their receptor,the cytokine receptor, you getdimerization up the receptor. Anactivation of this series of secondmessenger signalling pathways ultimateeffect of being creation of stackmolecules that cross into the nucleus andalter transcription of proteins. Thisparticular example is very important incancer biology we know that cytokinemolecules can contribute to the growth ofcertain tumors. Inhibitors of cytokinesectors are currently been evaluated for

the potential utility in a wide range ofdifferent cancers. The third example iswhere a signal, again binding, is bindingto the extra cellular domain of thereceptor. But in this case it's bound to atyrosine kinase, which it activates.These, not too surprisingly, are referredto as receptor tyrosine kinase. Again,another huge area of drug discovery forcancer chemotherapy. So to describe thisin the same manner as I described theprevious two types of receptor. Thisreceptor has an extra cellular hormone

binding domain. A cytoplasmic, enzymaticdomain typically a tyrosine kinase. Sohere the tyrosine kinase is a component ofthe receptor itself. In the cytokinereceptor example, the tyrosine kinase wasrecruited after receptor activation, so animportant distinction. The signal withinthe example of receptor tyrosine kinase,the signal typically a hormone or a growthfactor binds again to the extracellular


13/15

domain of the receptor and activates theenzyme. Upon the ligand binding, and I'llshow you a picture in a, in a second. Thereceptor converts from its inactivemonomeric state to a dimeric state.Exactly the same steps as the cytokinereceptors. In which two polypeptides,receptor pol ypeptides bindnon-covalently. The cytoplasmic domains inthis example, become phosphorylated onthis specific tyrosine residue. And theirenzymatic activities are activated as aresult of phosphorylation. This ultimatelyresults in phosphorylation of a series ofsubstrate proteins to bring about theultimate response. Natural endogenousligands for receptor tyrosine kinaseinclude epidermal growth factor andinsulin. As I said previously, inhibitorsof receptor tyrosine kinase are becomingwidely used and are under furtherevaluation in the setting of a cancerchemotherapy. So here is the picture andyou can appreciate that on the left hand

side this looks somewhat similar to thecytokine receptor. The difference, ofcourse, here is you have your ligandbinding to the extra cellular domain, butupon binding. You see here that the, thebinding results and dimerization but hereyou can see the, here you can see theexample of phosphorilation occurring,ultimately of the tyrosine residue tobring about a second messenger signalingpathway. The fourth example is that thesignal binds and directly regulates theopening of an ion channel. So I'm sitting

here talking to you today. I'm hoping,hoping that you're listening. In order foryou to be able to listen, your autonomicnervous system needs to be in top action.You're concentrating, at least I hopeyou're concentrating. The receptors thatare involved in mediating your ability totry and concentrate include ion channels.So let's talk about this fourth type ofreceptor. So these are commonly referredto as ligand and voltage gated ionchannels. Many useful drugs in clinicalmedicine today work by mimicking or even

blocking. The action of natural ligandsthat regulate the flow of ions throughplasma membrane channels. Those of you,who have taken physiology before,appreciate that action potentials acrossmembranes is particularly important inneuro transmission. The ability forsodium, potassium, and calcium is just fewexamples of naturally occurring ions invev o are necessary for normal neuro


14/15

transmission. Ion channels are typicallycomposed of several sub units. The ligandagain, in this example binds to anextracellular domain on one of these subunits of the receptor. And when thatligand binds to a sub unit in the ionchannel receptor, it opens up a centraltrans membrane typically aqueous ionchannel, and allows the passage of the ioninto the cytoplasm. Again the commonexamples are the neuro transmitters,seratonin, asetilkolin and glutamate solets look at the picture. So in this partof the diagram, we have essentially slicedopen the receptor in a longitudinalfashion. And you can see in thisparticular example four sub units. Thereare in fact five sub-units for thisparticular receptor but we've removed theone most proximal to us. So here we cansee a deception of four different subunits each with Greek suffix lettering.This is an example of the nicotinicreceptor. Nicotinic receptors mediate the

effect of the neurotransmitterasetilkolin. And you can see that thisreceptor spans the plasma membrane. Itliterally sits on the plasma membrane. Andwhat we are attempting to show you in hereis that, this is where the passage of theions occur. So the ions are eve, they aremoving from an intracellular to anextracellular location or vice versa. Andit is the regulation of this aqueous poredown the center of this channel nowpermits or inhibits the flow of enzymesfrom the, the flow of ions from the

extracellular to the intracellular domain.It might help you, by looking at thisparticular, graphic insert on this slide.This is now looking at the receptor fromabove so looking down into the receptor,this section here is the aqueous porethrough which ion transport needs tooccur. And the aqueous pore is surroundedby these five sub-units as shown for theexample of the nicotinic receptor. So,binding to these receptor, asetilkolin inthis example, binding to the alphasub-unit of this receptor opens up the ion

channel. And allows the transport in thisexa mple of sodium ions. But we have manydrugs that actually function asinhibitors, that prevent the opening ofthe ion channel, and thus prevent thetransmission of ions resulting in manycases in hyper-polarization of cellmembranes and diminished pharmicodynamicresponses as a result of the agonistbinding to the receptor. So, so far we've


15/15

talked about four transmembrane signalingmechanisms. We're going to end there fortoday's class. And in the next section,section number seven, we will introduce Gcoupled protein receptors and do an indepth discussion of those. Thanks forattending class today.

1-8-7.Drug Action.txt

Documents

Transcript of 1-8-7.Drug Action.txt