G-protein Coupled Receptors – Second Messenger Systems

by Georgina Cornwall, PhD

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    00:00 So G-protein coupled receptors are where we're going to go next. These are the largest category of receptors in animal cells. And recall, they are involved in metabolic and structural changes as opposed to the receptor tyrosine kinases which were involved in just the general daily function of cells for the majority of the time. So as we look at G-protein coupled receptors, we have G-proteins involved. What are G-proteins? G-proteins are proteins that are activated by GTP, right.

    00:39 So, in this case we have a ligand and it binds to its receptor. This is the first messenger.

    00:46 And that receptor is going to activate a G protein. And the G protein goes somewhere else entirely to activate another effector protein. That effector protein is often embedded in the membrane and that effector protein will activate a second messenger. Really what we're doing here again is passing on phosphates to activate proteins further and further down in the cascade.

    01:14 As we activate that second messenger, it can run out and activate all kinds of kinases to have all kinds of cellular effects. So a general example of how this work seems pretty similar doesn't it to the receptor tyrosine kinase cascade. Although it's different in its specifics.

    01:35 Now we're ready to look at some specific second messenger systems. First of all, keep in mind that the G-protein is the piece that links the receptor that's embedded in the membrane to the effector protein which is also often embedded in the membrane. And that the effector protein is what produces the second messenger that runs off and has all the effects throughout the rest of the cell.

    02:00 So first, a cyclic AMP second messenger system that's mediated by adenylyl cyclase. Adenylyl cyclase is the effector protein and cyclic AMP is the second messenger. Here you have a receptor for a molecule. The molecule binds to the receptor and activates a G-protein. In this case, the G-protein has three subunits. And it's the α subunit that will activate adenylyl cyclase.

    02:33 The β and γ subunits have the opportunity to go off and activate a completely different protein cascade.

    02:40 So you can see that one receptor could have many other effects but we'll stick with the adenylyl cyclase cascade and the α subunit activating that. Now we can activate the second messenger where ATP comes in, drops off some phosphates and forms cyclic AMP, adenosine monophosphate.

    03:04 Adenosine monophosphate is the second messenger in this system. And it will go on to activate protein kinase A. We shorthand that as PKA. Protein kinase A is activated and that will go on to activate many more proteins perhaps with some signal amplification and we'll have our cellular response.

    03:27 The cellular response depends on what other proteins are activated. So, it could be different but this mechanism comes into play multiple times throughout Biology. So it's a very popular signalling system so to speak. Let's now look at phospholipase C, another G-protein mediated pathway.

    03:51 In the case of phospholipase C, we have that as the effector protein. This effector protein though activates a couple of other second messengers. So in the phospholipase C system the signal molecule ligand binds to the receptor. Activates the same sort of G-protein which has three subunits.

    04:17 We've got α, β, γ. α also can activate the phospholipase C. And PIP2 is a protein.

    04:28 It's a shorthand for protein that is going to be the substrate giving phosphates to this adenylyl cyclase.

    04:36 And it's going to form diacylglycerol as well as inositol triphosphate or IP3.

    04:45 And these two second messengers are now able to activate a variety of cellular processes.

    04:53 In this case, IP3 is going to activate the release of calcium from the endoplasmic reticulum.

    04:59 If we're in a muscle cell, it's the sarcoplasmic reticulum. But either way we're going to release calcium which is going to result in muscle contraction. However if this system is happening in an endocrine cell, it's not interested in having any muscle contraction, it's interested in releasing hormones. So this very same signalling mechanism with IP3 is going to allow release of hormones from hormone producing cells such as the pituitary gland or adrenal gland. Different proteins can have different effects in different cell types. So, let's say that you need to run away from a big mountain lion. Probably not the best idea but if you need to get out of there, we're going to activate the fight or flight system, right. Epinephrine or adrenaline is present and we need some sugar to get away. This is an example where two different signal molecules act on the same pathway having the same effect. So, epinephrine binds to its membrane receptor and a G-protein activates the second messenger. And glucagon involved in releasing sugar also binds to its receptor and has the same effect. So both of these signal molecules are binding to different receptors yet having the same effect inside the cell. On the contrary, we can see that one signal molecule could have very different effects. For example, in this case epinephrine. We're trying to run away again.

    06:39 We need to increase our heart rate but we are not interested in digesting food at this point in time.

    06:45 So epinephrine will end up in the heart muscle creating adenylyl cyclase that increases the production of cyclic AMP, the second messenger. And the cyclic AMP increases the contraction strength. So that's the effect for the full cells there. But while we're still running from this mountain lion, we have our gut and we do not really need to be putting a lot of energy into digesting food at this particular moment.

    07:14 So, a different G-protein modulates this process in which we see that G-protein inhibiting adenylyl cyclase. So grabbing on to that enzyme and stopping it producing cyclic AMP, and so then we have relaxation of those muscle cells. So one signal molecule having different effects in different cells or you could have multiple signal molecules having the same effect in the same cell.

    07:42 So it's a very diverse system of cell communication and control of cell functions.

    About the Lecture

    The lecture G-protein Coupled Receptors – Second Messenger Systems by Georgina Cornwall, PhD is from the course Cellular Structure.

    Included Quiz Questions

    1. MAP kinase cascades for signal amplification
    2. Molecular switches that connect pathways
    3. Multiple cellular targets resulting in many cellular effects
    4. Reduction in signal from reverse kinase cascades
    1. ...are the proteins that are activated by the G-protein to make the second messenger
    2. ... could be adenylyl cyclase or Phospholipase C
    3. ...could be cyclic AMP and PKA
    1. …adenylyl cyclase.
    2. …guanylyl cyclase.
    3. …phosphokinase
    4. …protein phosphatase
    5. …protein diphosphatase
    1. The DAG and IP3 are the signal-carrying molecules which bind to the cell membrane receptor during muscle contractions.
    2. The phosphatidylinositol-4,5-bisphosphate (PIP-2) is a membrane phospholipid embedded in the inner leaflet of the cell membrane.
    3. Diacylglycerol and inositol-1,4,5-triphosphate (IP3) act as second messengers in downstream signaling pathways.
    4. Phospholipase C enzyme acts as an effector protein and hydrolyzes the PIP-2 to stimulate the muscle cell contractions.
    5. The IP3 and DAG molecules stimulate the downstream signaling pathways to facilitate the release of hormones in the endocrine cells.

    Author of lecture G-protein Coupled Receptors – Second Messenger Systems

     Georgina Cornwall, PhD

    Georgina Cornwall, PhD

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