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Lecture 30

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Department
Biology (Sci)
Course
BIOL 300
Professor
Siegfried Hekimi
Semester
Fall

Description
th BIOL 300 November 19 2012 Lecture 30 Dr. Shock GPCRs can also regulate ion channels • Many neurotransmitters like seratonin can bind directly to ion channels and open them (i.e. ligand gated ion channels) • However, many others are able to bind GPCRs that either directly or indirectly (through second messengers) regulate ion channels The first example using a GPCR is the neurotransmitter acetylcholine, which acts in normal muscles cells as well as cardiac muscle cells • In skeletal muscles Ach binds directly to ion channels to open them • However, in cardiac muscles, Ach actually binds to a GPCR (muscarinic acetylcholine receptor) whose beta-gamma subunit actually binds to a potassium channel and opens it • This is only of the only examples where the beta- gamma subunit is the one that carries out the activation (and not the G-alpha) Let’s say you know that acetylcholine binding to a GCPR leads to an efflux of potassium from the cells, but nothing else; how would you go from there to learning that it’s actually the beta-gamma subunit that carries out the activation of the ion channel and not the G-alpha? • If you create a null G-alpha mutant, you would discover for this receptor that the potassium channel is still able to open without the presence of G-alpha • Since the alpha subunit is almost always the activating protein, this result was very unexpected • From this, you could formulate the hypothesis that it’s G-beta-gamma that opens the channel; you could then prove this by: • First by knocking out the G-beta-gamma gene and seeing if it stops opening of the potassium channels • Then transfecting the G-beta-gamma gene into a cell line that has the potassium channels, but not the GPCRs, at which point you would expect a change in the membrane potential of these cells The other famous GPRC pathway which modulates ion 1 th BIOL 300 November 19 2012 Lecture 30 Dr. Shock channels is in vision. In our eyes, most of the photoreceptors present (95%) are rods, which are good for black and white vision and motion detection, while only 5% of them are cones (for color vision) • This would lead to assumption that rods are more important, but in fact we use the cones most in our lives because we see in color • Hunters or people that live in the dark a lot would make a lot more use of the large rod distribution Within these rods are membrane stacks which contain rhodopsin, a GPCR which does not bind a ligand per say, but changes its conformation based on the amount of light present (you could say that light is the ligand) We don’t need to know the structure of the retina, but one thing to note is that light actually comes from the opposite side to where the photoreceptors are (a design flaw in evolution) • Because of this, the photoreceptors are actually covered by layers of cells and axons (like a camera whose lens is blocked by a bunch of wires) • This is a product of evolution and can’t really be reversed, we kind of just have to deal with it This pathways works opposite to the typical pathway we are used to; neurotransmitter is relapses to the axons during the dark, while detection of light by rhodopsin actually causes neurotransmitter release to drop. Retinal is a light- detecting molecule which is covalently anchored to a GPCR; the whole thing is referred to as rhodopsin • Light, coming in as photons (one photon is enough for a reaction), will cause a conformational change in the molecule which will lead to activation of the GPCR • The minimal amount of energy you can get from light is one photon, which is enough to activate rhodopsin Rhodopsin will become active, which will in turn activate G-alpha • G-alpha-GTP then activates a phosphodiesterase by binding to its inhibitory subunits 2 th BIOL 300 November 19 2012 Lecture 30 Dr. Shock • This causes conversion of cGMP into GMP, which causes cGMP to dissociate away from cGMP gated sodium channels which then close • Therefore, the sodium channels are actually open in the dark (when rhodopsin is inactive) and closed in the light (when rhodopsin is active) • cGMP binding to the gated sodium channel is again cooperative (like cAMP with PKA); you need 4 cGMPs per sodium channel • cGMP will eventually be replenished by guanylyl cyclase, which turns GTP into cGMP (the analog to adenylyl cyclase), at which point the channels will be able to open again Once again, the signal coming from photons (which is very small, as small as one photon) need to be amplified to closing of hundreds of sodium channels, to the change in membrane potential significant enough to fire action potentials. The presence of light will cause a conformational change in rhodopsin which causes alpha helices in the GPCR to shift to a more narrow angle with respect to one another, which allows activation and release of G-alpha • Very similar things happen in other GCPRs, the only difference is that the conformational change of the receptor is caused by binding of different ligands Visual adaptation works over a 100,000X range of light levels (between a completely dark room and very bright environments) • If this adaptation was not there, we would not be able to see in a wide range of environments We are constantly able to adapt our rhodopsin depending on 3 th BIOL 300 November 19 2012 Lecture 30 Dr. Shock levels of light; this is don’t through the same desensitization/adaptation mechanisms we already talked about • If the event of little light, rhodopsin is very sensitive and is activated by very little light in order to help you see in the dark • In very bright places, a protein called rhodopsin kinase will phosphorylate rhodopsin in order to decrease the sensitivity of the receptor (i.e. it takes more light to close the sodium channels) • In even more brightness, hyperphosphorylation of rhodopsin will cause biding of arrestin to completely inhibit binding and eventually cause degradation of rhodopsin, which can c
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