The GABA receptor | How does it work?

A short video on how benzodiazepines, barbiturates, BZ agonists like zolpidem, and how antagonists like flumazenil work. The focus is on the GABA receptor and an explanation of CNS depression. View the rest of my posted videos below:

(1) Pharmacokinetics Core concepts: http://youtu.be/CMRZqdrkCZw
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DRUG ABSORPTION Videos:
(2) Drug Absorption Overview: http://youtu.be/eya9jR3v7i8
(3) Bioavailability: http://youtu.be/rv2Rpdi7OHM
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DRUG DISTRIBUTION Videos:
(4) Drug Distribution Overview: http://youtu.be/DH2WGUd7MBs
(5) Volume of Distribution: http://youtu.be/B63sqUfvFQQ
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DRUG METABOLISM Videos:
(6) First Pass Metabolism: http://youtu.be/5AB8WkCbz4k
(7) Phase I Metabolism: http://youtu.be/GGLddVpVg9M
(8) Phase II Metabolism: http://youtu.be/iIWAUo05GFE
(9) First Order and Zero Order Kinetics: http://youtu.be/XEotDfKhNTw
(10) Drug Half-life: http://youtu.be/eTqPsqnbwoc
(11) First-order elimination rate constant: http://youtu.be/De9999Jj-5Q
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DRUG ELIMINATION / EXCRETION
(12) Drug Clearance: [not yet posted]
(13) Practice problems: [not yet posted]
(13) Dosage Regimens: [not yet posted]
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Factors That Affect Drug Metabolism:
(14) Enzyme Induction: http://youtu.be/Dtbkc8F_ff0
(15) Competitive Inhibition Overview: http://youtu.be/iNIxMuHuL3w
(16) Competitive Inhibition of Statins: http://youtu.be/Lt1-mjMFniE
(17) Acetaminophen toxicity (Clinical Correlate): [Not yet posted]
(18) Pharmacogenomics Overview: http://youtu.be/3vZxbX5P9TU
(19) Slow Acetylators - Pharmacogenomics: [not yet posted]

And the last part here before we jump into these drugs is the structure and function of this GABA Chloride Ion Channel

that we can see right here.

So just taking a first look at it right, this is a GABA Chloride Ion Channel

and the neurotransmitter is GABA.

Now, I didn't mention this earlier because I didn't want to overwhelm you.

but notice here, it's not just 1 GABA that needs to bind but actually 2 GABAs need to bind in order to let an ion through here.

So I'm just going to write a neurotransmitter x 2.

What is this receptor called?

Well it's called the GABA A receptor

and the reason it's called the GABA A receptor is due to the actual type of sub-units that comes through that comprises this channel

and also, the ion that goes through it.

And we'll talk about GABA B on the next slide.

What is the ion here?

Well, the ion is called Chloride.

And so, what happens?

Chloride comes into the cell and it makes the inside of the cell slightly more negative

and the effect of that is an inhibitory post-synaptic potential.

So, let's put these all in context

because it's kind of confusing unless you see it all together.

So let's just say here is my pre-synaptic neuron

and let's say here's my post-synaptic neuron.

Now, I'm going to draw this a little different than you might see it

because we're going to add something to it here in a second.

So what's going on here?

Well, we've got a different color.

So we have an action potential right. It comes down the cell. We have this voltage gated calcium channel,

this allows calcium to come in right.

And so, calcium comes in and it causes the fusion of these vesicles and what are these vesicles containing?

They're containing GABA.

And so, from this pre-synaptic neuron, these vesicles traverse across the synaptic cleft and they will bind to a receptor on the post-synaptic membrane.

So let's just say here is the ion channel, here is the receptor.

That's what we're looking at right here.

That receptor is that one here.

So here's step one, action potential comes. Two, calcium comes in. Three, we get the fusion GABA and four, it diffuses across.

Five, it binds to the receptor and that's what we're seeing here.

And so six would be the Chloride ions that are here coming into the post-synaptic neuron causing an inhibitory post-synaptic potential

and so, that's what we see right here.

Now, this isn't the only neuron that's interacting with this post-synaptic neuron right?

We can also have an excitatory one that's synapsing here as well.

So, I'm not going to draw everything like I did before but let's say we have all of these steps

but instead of GABA coming here, let's say we have (man! it's crazy how nice colors look) let's say we have glutamate. That was a silly comment.

And so, with glutamate right it also binds to its own receptor

but in this case, let's say, it lets sodium in and now, we have an excitatory post-synaptic potential.

And so, what this cell is doing is it well it says, okay, is there more positive or is there more negative?

If there's more positive, is it enough to reach threshold?

And if there is, then maybe I'll list another action potential here

and here are these you know sodium channels on the axon that allow charge to come through.

Remember anywhere you block along this path, well you can mess things up.

So this can also be represented with a little diagram here.

And so, when I say that the sedative-hypnotics have dose dependent CNS depressant effects,

this will kind of explain why.

So right off the bat, we can - let me give us, what's our color? Let's go back to orange.

So here, let's say we have this excitatory stimulus. let's say this was glutamate.

It was enough to reach threshold. We kick off. Boom! And all our non-action potential and we come back to resting membrane potential

but now we get this inhibitory stimulus, okay so this let's say is GABA

and this GABA caused a dip in this membrane potential.

Now the next time this excitatory stimulus comes along glutamate, it is not enough to reach threshold

and as a result, we get the CNS depression.

The depression is a result of no more communication or decreased communication.

And so, if this guy overwhelms here, we're not going to get this action potential

and therefore, we're depressing the central nervous system.

Makes sense?

All right, so let's take a moment and look at the receptors for the different neurotransmitters and drugs here.

So the first thing you should notice is we have GABA here, we have the benzodiazepines here and we have the barbs here.

And so, these are all binding at distinct locations and if you can't tell from this kind of cross sectional view,

maybe a top down view might be a little better

So we have GABA which is the endogenous neurtransmitter

and by convention, the endogenous neurotransmitter typically binds to the alpha sub-unit.

Here we have our Benzodiazepines represented with a bz and this binds to the alpha and gamma sub-unit that we can kind of see right here.

This was alpha, this was gamma.

And here, we have our Barbs and our Barbs are binding to the beta and gamma sub-unit.

So what's important here is that they're not the Barbs and the Benzos, they're not competing for the same binding site

and as a result, they can have additive effects.

Okay, it's important to know that they're not competing.

Also, there's a lot of heterogeneity even within this GABA receptor. This GABA A receptor

And in particular, notice that the benzos are binding here and this binding site actually has a name

and we call it the bz 1 receptor and this is probably due to the fact that there's this alpha 1 sub-unit here.

Now, the only reason I mentioned this, you don't need to memorize the exact molecular make-up of the

but some of our newer hypnotics are very selective for this bz 1 receptor with this alpha 1 sub-unit.

Newer hypnotics are selective and because of the location of these receptors, we can get these hypnotic effects

which is making you sleepy without as much of the anxiolytics effects

and that's kind of one of the benefits of these newer hypnotics.

So you get more hypnotic effect with less sedative effect

and we can see that right here. This is Ambien or Zolpidem.

and the last point I want to make is not only do we have selectivity for you know particular binding sites but also for ions.

So this is the GABA A chloride ion channel right but we also have a GABA B channel

or a GABA B I guess potassium ion channel. GABA B.

And so, unlike this which allows chloride to come into the cell, this GABA B lets potassium out.

and the drug that interacts most with this receptor is Baclofen which is a spasmolytic

and you would use that for muscle spasms and we probably won't talk about Baclofen again

but it's just an important thing to know right here.

Finally, one last point while we're looking here. We have this guy right here, Flumazenil.

And notice where it is. It's right here for between the benzos and the newer hypnotics but nowhere near where the Barbs are

and so, what this is, is actually it's an antagonist. I can't write it all out but let's write it here.

And so, this is special and that is it can reverse the effects of overdoses from Benzos or Zolpidem

and won't have any effect on the Barbs because they have different binding sites.

So again, understanding the structure will really tell you the function of how this work

and that my friends is sedative-hypnotics, the foundations.

On a last little thing here, here are some questions that hopefully you should be able to answer having attentively watched these lectures.

So it's learning the objectives with homework questions.

Feel free to do these on your own.