Hello everyone and welcome back.
In the last section we began our discussion of different types of receptors
and how they work. In this section we continue with that discussion and
begin talking about a specific set of receptors which are what we call
guanine binding proteins, or what are called G-protein receptors. This
lecture is also going to be broken into two parts. This first section is
going to cover an overview of what G proteins are and how they work. The
second section will talk about specific types of G proteins, specifically
the GS, the GI, GP, and other types of G proteins. So, let’s begin by
starting with slide two and get a little bit of background about what G
proteins are and how they work.
In general, G proteins consist of three sub-units that are bound to a
receptor site; the alpha, beta, and gamma sub-units. The beta and gamma
sub-units are usually considered to be one complex. So, when we talk of
them, I will talk of them primarily as the beta sub-unit rather than beta
gamma. The alpha sub-unit is loosely associated with the receptor membrane.
It is usually the coupling agent between receptors and what we call primary
effector enzymes. These are the enzymes that are going to be involved with
doing things with inside a postsynaptic element. There are more than 12
different types of alpha sub-units, and each has a different action and
name. There are many, many more. We just don’t know what they are yet.
The alpha sub-unit also contains a variety of different
types of receptors. As we can see here, they bind on a variety of things
such as the guanine receptor, glutamate receptors, neuropeptide receptors,
and on and on. Interestingly, they also are involved with (can’t understand)
which is an extremely important in color vision within the eye.
On slide five we see the beta-gamma complex. This
structure is more tightly fixed in the membrane. But it can affect ion
channels directly and we’ll talk about that in more detail a little bit
later.
Now in addition to the alpha, beta and gamma sub-units,
there are a variety of other important structures within the post-synaptic
element that are related and involved with G proteins. The first of these is
shown in slide seven. This is what is called adenylyl cyclase or what is
also called the adenylyl cyclase. It is usually activated by the alpha
sub-unit of a GS protein. When it’s activated, it makes Cyclic AMP from ATP
As you can see there’s an alpha binding site located upon the adenylyl
cyclase. Cyclic AMPis what we call an intracellular messenger (or second
messenger). This compound goes and binds on other structures that cause them
to do things.
Now one of these other structures as we see in slide eight
are what we call protein kinases. There are a wide variety of different
types of protein kinases but they all kind of work the same. They have four
sub-units that consist of two regulatory sub-units where Cyclic AMP or other
types of enzymes will bind, and two catalytic sub-units which puts phosphate
groups on different types of ion channels. The catalytic sub-unit is the
working part of this enzyme.
In slide nine, there is an overview of how G proteins
work. The first thing that’s gong to happen is there’s going to be some kind
of an external signal. This is what we call usually a first messenger. First
messengers can be a wide variety of things but we usually think of them as
neurotransmitters. The neurotransmitter is going to bind to some kind of
receptor site. That receptor site is going to have some kind of transducer,
in this case a G protein. The G protein is then going to have an effect on
some structure (called the primary effector). That structure, then makes a
second messenger which is going to bind to some other structure and cause
something to happen. So, second messengers bind on what we call secondary
effectors or some kind of structure.
Now let’s talk a little bit about G proteins at rest. This
classic example is shown in slide 10. We see a variety of different things.
First of all we see a receptor binding site. Connected to that binding site
are the alpha and beta sub-units, and attached to the alpha sub-unit is a
binding site. This binding site is for what we call guanine triphosphate or
what is also called GTP. GTP, through a process which we’ll talk about in a
little bit, is ultimately converted to GDP. So, at rest, what we actually
see here is GDP occupying the binding site when the membrane is at rest. GDP
has to be located on this binding site for the alphas, betas, and the
receptor binding site to be connected to each other. If the GDP is gone,
other things happen (as you’ll see in a minute).
So, what happens,. Well as we see in slide 11, when we get
some kind of stimulation, the neurotransmitter causes a conformational
change in the receptor site. What this does is knock off the guanine
diphosphate. As a result, it leaves an open alpha binding site (shown
figuratively on slide 12). So as we see, we have some kind of stimulation,
the neurotransmitter is bound on the receptor site and as a consequence of
that, the guanine diphosphate leaves. In essence, it is kicked off.
Now what we have, (as we see in slide 13), is an alpha
unit with an open binding site. This alpha binding site has a high affinity
for guanine triphosphate. So, as a result of that, guanine triphosphate is
going to bind to this open binding site. As a result of that (as we see in
slide 15), it causes a conformational change. When we get this
conformational change, we get disassociation between the alphas with the
guanine triphosphate on it, the betas, and the receptor sites in general.
So, what we have are free alphas and free betas that can go around and do
something. And an example of one of these somethings’ is the activation of
adenylyl cyclase. As we can see in slide 16, the alpha binding site is going
to be there, and when it’s occupied it makes Cyclic AMP from ATP. So, what
will happen is that an alpha will bind on that binding site of the adenylyl
cyclase and when it does that, it causes that adenylyl cyclase to begin
making cyclic AMP (which will then go and do other things which we’ll talk
about a little bit later).
Now there’s one thing that happens in this process of the
alpha being on the adnetylyl cyclase. What will happen is that when alpha is
bound on the adenylyl cyclase it causes the guinine triphosphate to become
what is called a guanine diphosphate. What a phosphotase does is knock off
phosphate groups. So, basically what the phosphotase does is convert the GTP
to GDP. As a result of that, it basically breaks the bond from adenylyl
cyclase. So guanine triphosphate is going to be converted to GDP. Thus, it
no longer looks the same to the adenylyl cyclase. As a result, it breaks
apart from the adenylyl cyclase. Since it now has the GDP on it, it rebinds
with the beta subunits. As a result (by that time the neurotransmitter’s
been removed from the receptor) they relink back to the receptor site and
the process repeats itself.
Protein Kinases, as again we discussed a little bit ago)
have a wide variety of different types. As we can see in slide 18, they
basically put phosphate groups on something. Where? A protein; and
specifically an ion channel. As a consequence, they’re called protein
kinases and there are many, many types. Again as we see in slide 19, they
have four regulatory sub-units, four sub-units to regulatory where your
Cyclic AMP is going to bind (or some other enzyme) and two catalytic
sub-units, which actually puts the phosphate group on the ion channel.
So, this is kind of an overview of the way that G proteins
work, primarily stimulatory proteins. In the next section we’re going to
talk about how specific types of G proteins work, that is the GS, GI, and GP
proteins. Essentially they all follow a very similar pattern, it’s just that
different things happen when they become activated. The reason that these
are important is because this is where a lot of different types of drugs are
being targeted at to control different types of disorders, including things
such as schizophrenia and depression. Further, G proteins are also important
because this is where a lot of different types of drugs including illicit
drugs work as well. The classic example is marijuana.
So, until we meet again, what I’d like you to do is walk
back through this again if you need to. In the next section we will continue
on and talk about specific types of G proteins. I would suggest that you do
this right now following this particular lecture so it’s kind of clear in
your mind about how they work. Until then, we will be thinking of you
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