G-Protein Coupled Receptors (GPCRs)

by Kevin Ahern, PhD

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    00:01 So far I’ve talked about receptor systems that are functioning in fairly general terms.

    00:07 Let’s take a look up close and personal now at individual receptor system known as the G-protein coupled receptors, or as people refer them, the GPCRs.

    00:17 The GPCRs are G-protein coupled receptors, are a very abundant class of receptor proteins.

    00:24 There’s almost 800 genes in the human genome that are specifically in the form of G-protein coupled receptor sequences. Amazingly, almost 460 of these are olfactory, meaning that they’re involved in the process of smelling. So the GPCR depicted here is embedded in a lipid bilayer. And we’ve used color to identify the different regions of the protein projecting through the lipid bilayer. Though at the bilayer of course is shown in grey. The protein embedded in it has the different colors of blue, green, yellow and red. We see numbers associated with those and we see different colors associated with those. So each change of color represents a different portion of the protein that’s going from either down to up, or up to down, or down to up, and up to down, etcetera. This protein traverses the lipid bilayer by moving seven times up and down and up and down. So those are known as seven transmembrane domains and that’s where the name 7TM comes from. We can see that the protein has two distinct endings. One ending at the top that has a NH3+, that’s the amine end of the protein. And a carboxyl end of the protein in red at the bottom. Now, this orientation of the protein and lipid bilayer is specific for each individual protein. Now, the β-adrenergic receptor that I want to talk about is an example of one of the seven TMs, and it’s involved in working the process of managing the glycogen metabolism of the cell. So GPCRs get their name from the fact that they’re G-protein coupled receptors. So it’s appropriate I should say a little bit about what G-proteins are and how they work. So G-proteins are small proteins that bind to guanine nucleotides, that’s the G part of their name.

    02:08 The two different nucleotides that they can bind are known as GDP or guanosine diphosphate or guanosine triphosphate, GTP.

    02:17 We see in the example shown on the screen that the G-protein is shown as three units - an alpha (α) unit, a beta (β) unit and a gamma (γ) unit.

    02:26 This depicts what is called a heterotrimeric G-protein.

    02:30 And all G-proteins are essentially heterotrimeric, meaning they have three different subunits that are not the same in overall structure; this has the α, the β and the γ.

    02:41 Now these proteins associate with GPCRs.

    02:44 So the G-protein is associating with this membrane-bound protein.

    02:49 And they’re associating with it on the inside part of the cell.

    02:52 Remember the outside part of the cell is where the hormone binds, and the inside part of the cell is where the G-protein is located.

    03:00 Now, the G-proteins are actually altered by the GPCRs binding of hormone.

    03:06 You remember back in the slide that I showed you that the binding of the hormone changed the shape of the GPCR on the inside of the cell.

    03:14 It’s that change in shape of the GPCR that actually changes the G-protein that is associated with it.

    03:21 And we’ll see that in this slide here.

    03:24 So the G-protein is associated as we can see, and it’s what we call the resting state.

    03:28 The hormone has not bound.

    03:31 Epinephrine in this case comes and binds to the G-protein coupled receptor.

    03:35 And when it does that, it actually changes the shape of the G-protein coupled receptor.

    03:39 And I’ve kind of exaggerated it here by using a pentagon.

    03:43 The change in shape of the GPCR causes the interaction between the α subunit of the G-protein and the β and the γ subunits that change.

    03:54 The β and γ subunits are released, and in addition, the α subunit replaces the GDP that was in it with a GTP.

    04:03 Now that further facilitates the release of the γ and the β subunits.

    04:08 Well, one of the functions of the γ subunit is to actually help the α subunit to associate with the GPCR.

    04:15 When the γ subunit has gone away, then the α subunit is also now free to go away and it’s carrying GTP.

    04:23 Well GTP is an activation signal, it means that this individual α subunit has gotten information from outside the cell, communicated through the GPCR, and that α subunit is going to go, and it’s going to interact with other proteins, change their behavior and communicate that signal inside of the cell.

    04:47 We see that happening here.

    04:49 So now what’s going to happen is that the α subunit will interact with another protein and cause that other protein to create a second messenger.

    04:57 So here’s our activated α subunit with a GTP attached to it.

    05:02 The protein that the α subunit associates with is another membrane protein called adenylate cyclase.

    05:09 When the α subunit with the GTP binds to adenylate cyclase, adenylate cyclase is also changed.

    05:16 Now, what’s the change? Well the blue depiction here of the adenylate cyclase is the inactive form of the enzyme, meaning it’s not catalyzing any reaction.

    05:25 But when it’s car has been changed as we see here, that indicates that the enzyme has been changed in its activity.

    05:33 The change in the activity upon binding of the α subunit, causes production of a molecule known as cyclic AMP.

    05:41 And we can see the reaction depicted on the screen here.

    05:44 ATP is being converted into cyclic AMP.

    05:47 And cyclic AMP you may remember from an earlier slide, is a second messenger.

    05:51 This small molecule is now going to go to another part of the cell and cause the effect to be observed.

    About the Lecture

    The lecture G-Protein Coupled Receptors (GPCRs) by Kevin Ahern, PhD is from the course Hormones and Signal Transduction. It contains the following chapters:

    • G-Protein Coupled Receptors
    • GPCRs and G-Proteins
    • β-adrenergic Receptor Signaling – Creation of the Second Messenger

    Included Quiz Questions

    1. They often have seven transmembrane domains.
    2. They bind hormone with their intracellular domain.
    3. They are rare in the human genome.
    4. All of the answers are true.
    5. None of the answers are true.
    1. ...results in the production of cAMP by adenylate cyclase.
    2. ...causes the α subunit of a G-protein to become activated with GDP.
    3. ...stimulates the phosphatase activity of protein kinase A.
    4. All of the answers are true.
    5. None of the answers are true.

    Author of lecture G-Protein Coupled Receptors (GPCRs)

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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