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  University of Idaho
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  Psychology Dept.
  University of Idaho
  Design - P&D  CTI

Gs proteins are stimulatory proteins.  I have given you a breakdown of the procedure on slide two of how they work and what they do.  You can use this later to kind of follow along as we walk through the different steps of the Gs protein, what it is, and how it works.  The Gs protein pretty much follows what we talked about in the last section, the use of adenylyl cyclase.  Adenylyl cyclase makes CAMP as a second messenger which then binds on particular types of protein kinases.  But let’s talk about the sequence and how it works. So, let’s begin by going to slide three.

As we see in slide three, what we have is our receptor at rest.  The receptor has a binding site, it has GDP on it with its alpha and beta sub-units.  Then as we see in slide four, stimulation begins.  As a result of that, the GDP is going to leave and that’s going to leave an open binding site on the alpha sub-unit for GTP.  Thus, the GTP now binds on the alpha sub-unit and the alphas and the betas disassociate.  So, what we have are free alpha sub-units with GTP on it and free beta sub-units floating around.  Again, as we talked about last time, we have the structure called Adenylyl Cyclase and again, when activated, it makes CAMP from ATP.  The way that it’s activated is by the alpha S subunit.  So the alpha stimulatory subunit with its GTP on it binds to the Adenylyl Cyclase and when it does, the Adenylyl Cyclase begins to make Cyclic AMP.

Cyclic AMP then is going to float around and go to a Cyclic AMP dependent protein kinase.  And as we can see in slide 10, when the cyclic AMP binds to the regulatory sub-units, it causes the regulatory and catalytic sub-units to disassociate.  So now what we have are free catalytic sub-units floating around.  As we go to slide 11, what we see is when the catalytic sub-unit binds, it puts a phosphate group on an ion channel and causes the particular channel to open.  As a result you get depolarization.  If the depolarization is strong enough, you get an action potential in the next neuron.  So, now we’ve got these phosphate groups on this ion channel.  How do we get rid of it?  How do we shut the channel down?  Well, what we do is we have a substance called a phosphotase which knocks one or more phosphate groups off the other phosphates.   When it does, it causes a conformational change and the channel closes.

Well, what’s an example of a Gs protein?  Well, the classic example (as we can see in slide 13) is with the Gs protein having an effect with Norepinephrine.  The norepinephrine is going to bind on a beta adrenergic receptor, and as a result causes the Gs protein to activate adenylyl cyclase.  The adenylyl cyclase then makes cyclic AMP and of course, the cyclic AMP then binds on the cyclic AMP dependent protein kinase.  That protein kinase ultimately puts a phosphate group on the ion channel and the channel opens.  So in essence when you’re talking about norepinephrine metabotrophic neuron, this is an example of how that works. 

Well now we’ve talked a little bit about the GS protein.  Let’s talk a little bit about the next type of G protein.  These are what we call the GI proteins.  Gi proteins are first of all (as we see in slide 15) not the same as Gs proteins.  In essence, what they do is cause a decrease in cyclic AMP levels.  While the alpha subunits are different, the beta subunits of both the Gs and the Gi and even the Gp proteins are the same.  So, the alpha sub-units are different but the beta and gamma sub-units are the same.

On slide 16 we again provide a sequence for you to follow along as we walk through the different steps.  So let’s begin on slide 17 with these steps.  Again, what we have is we have a receptor binding site, but with this system, we have an alpha inhibitory subunit with a beta subunit and the alpha inhibitory subunit will have GDP bound to it.  So, in essence what we have is a receptor binding site at rest.  Again what happens?  Well the neuro-transmitter binds, it causes the GDP to leave, and now as we saw on the Gs protein, we have an open binding site. 

Again the GTP binds as we see in slide 19, and in slide 20 what we see is disassociation where we have free alpha inhibitory sub-units with GDP bound on them and free beta sub-units now floating around.  Now at the same time we’re going to also have an alpha stimulatory subunit (alpha S) or a Gs protein.  And again, the alpha S is going to be on the adenylyl cyclase with its GTP on it.  What’s going to happen is that GTP is going to be converted to GDP.  When that occurs, there’s a beta there immediately ready to suck it up.  Where as we didn’t have as many Betas, it won’t suck up as rapidly and you get stimulation a little bit longer.  But, because we have so many betas in the system, every time that alpha S is converted (GTP is converted to GDP), it binds with a beta sub-unit.  As a result of the combination of these processes (as we see in slide 23) we get a decrease in cyclic AMP.  As a result of that, fewer protein kinases disassociate, we get fewer ion channels opening, and ultimately, what we get is less depolarization.  So the Gi protein is in essence designed to shut down systems or at least slow down the amount of the Gs protein stimulation that may be going on out there.

Now, we have another type of G protein and these, as we can see in slide 24, are what we call Gp proteins.  The P meaning Phosphoinositol.  As you see here, Phosphoinositol has a basic structure with a fatty acid complex, with an inositol combined to it (phosphate group).  We can then phosphoralate it two more times, and what we get is triphosphoinositol and as a consequence of that, we have a fatty acid complex and inositol with three phosphate groups bound on it.  So, as you can see here, we have a couple fatty acids on a carbon backbone and we have an inositol surrounded by three different phosphate groups. 

Slide 27 walks you through the sequence that we’ve done in the past with the GS and GI protein, so let’s kind of walk through it here.  Again as we talked about, the neuro-transmitter’s going to bind to the receptor, the GTP leaves and the GDP binds.  And as a result, the alpha P and beta subunits disassociate.  As a consequence, we have free alpha P subunits and free beta subunits floating around.  Well what happens, what does the alpha P do?  Well, the alpha P sub-unit activates an enzyme that’s located within the postsynaptic element that is call Phospholipase C (Phospholipsase C also has a wide variety of forms as well).  Essentially, what the phospholipase C does is split the triphosphoinositol and breaks it into two groups:  Diacylglyceral (DAG) and IP-3 systems.  This is shown on slide 28,.  Where you have the breakage of the DAG that is the carbon backbones with the two fatty acids from the inositol (I) surrounded by three phosphate groups P3. 

Let’s talk about the IP-3 system first because it’s very important.  The IP-3 system is basically releaser of calcium from smooth endoplasmic reticulum that we have in the post-synaptic element.  As a consequence, what we get is a surge of intracellular calcium in the post-synaptic element.  Now, this isn’t working the same as the calcium that we talked about in the presynaptic element.  The calcium there basically came in from the outside of the pre-synaptic element.  In the IP-3 system, the intracellular calcium is located with inside the post-synaptic element.  Relatedly, what ends up happening is that the calcium is going to bind with another substance called Calmodulin.  Calmodulin (abbreviated CAL) combines with the calcium and the combination of the two stimulates what we call a calcium calmodulin protein kinase.  The calcium calmodulin protein kinase then goes and phosphorlates an ion channel.  It works the same way as the other protein kinases that we’ve talked about in the past.  As a result, we get depolarization.  Again, what we see in slide 30 is the calcium calmodulin protein kinase has the two regulatory sub-units, the two catalytic sub-units.  It just has a different binding site on the regulatory sub-units for the calcium calmodulin.  Again (as we can see in slide 31), when the calcium calmodulin binds it causes the protein kinase to split, the catalytic sub-unit puts a phosphate group on the ion channel, and you get depolarization. 

The DAG system, on the other hand, works a little bit differently.  As we can see on slide 33, DAG binds specifically with another kind of protein kinase (called protein kinase C). 

So now we’ve talked about three different types of protein kinases.  We’ve talked about the Cyclic AMP protein kinase, the calcium calmodulin protein kinase, and now we have protein kinase C. 

In essence, what protein kinase C does is change the affinity for calcium.  As a result, the calcium binds with the protein kinase C and causes phosphorlation.  As a result, we get the channel opening and depolarization again.  So, as we see in slide 34, it looks exactly the same as the IP3 and other types of protein kinas.  Again, when DAG binds on the regulatory sub-units, you get disassociation and the resulting catalytic subunit putting a phosphate group on the channel.  The classic example of this is the Ach muscarinic receptor, which basically is going to activate phospholipase C and then, which breaks up IP3 and DAG. 

Now, there are other G proteins as well and I’m not going to really talk about them as much, but I just want to discuss a couple.  One is the Arachidonic Acid system.  It uses the system of histamine as a primary receptor.  So, histamine is going to bind on the histamine receptor, it stimulates the G protein, and ultimately breaks down and causes a second messenger of arachidonic acid to be converted.  Then it causes a wide variety of other effects.  As you can see here in slide 41, there’s a wide variety of sites of actions for this type of system. 

So, as we see in slide 42, there are many, many types of G proteins.  This is the hottest area of neurophysiology and neurochemistry right now.  If we can figure out how these proteins work, we can develop different types of compounds that bind in different location sites.  As a result, cause you to stop being schizophrenic or depressed or whatever problem that you may be having.  These systems are also affected by a lot of different psychotropic drugs.  For example, marijuana is a very, very potent binder on the adenylyl cyclase binding site and causes a wide variety of different effects.  It also binds on other structures as well. 

So again, G proteins are the hottest stuff that’s going on right now and if you’re very good at identifying what’s going on, not only will you win your Nobel Prize, but you’ll make lots of money from different drug companies as well.  In the next and last section we’re going to begin discussing different types of disorders that are related to physiological psychology, so we look forward to talking with you about those disorders and will talk with you soon.