BIS104 Note7

BIS104 Note7 - Lecture 7 Bio Sci 104 G-protein-coupled...

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Lecture 7 1 Bio Sci 104 Winter 2010 G-protein-coupled receptors I. Cell-cell interactions mediated by G-protein-coupled receptors A. Represent the largest family of cell surface receptors . G-protein-coupled receptors respond to broad variety of signals, including hormones and neurotransmitters. (Very common- thousands of d ifferent G-protein coupled receptors in humans. Half of known drugs work through G-protein coupled receptors.) a. Despite a wide diversity in the nature of the ligands (ranging from proteins and small peptides, to single amino acids and fatty acid derivatives), the G- protein coupled receptors themselves all share significant sequence similarities. b. They consist of a single polypeptide chain, which crosses PM seven times-also known as " serpentine receptors ". c. Extremely conserved in evolution (many homologues in many species): (FYI: one example, the a and α mating factor receptors in yeast are members of this same family.) d. The same general structure is also found in rhodopsin, which transduces light signals in vertebrate eye, and in olfactory receptors in nose. B. The extracellular domains bind to ligand and initiate the signal. This signal is transduced across the membrane, where it is coupled to the trimeric-G proteins . C. Trimeric G proteins act as molecular switches that flip between two states- active (when bound to GTP) and inactive (when bound to GDP). (similar to Rab and Ran-related switches discussed before). 1. Step-by-step mechanism: a. The trimeric G proteins are flipped into their active state by interaction with a ligand-receptor complex (by inducing binding of GTP, leading to activation), b. they then transmit the signal to a downstream target molecule. c. Subsequently the GTP is hydrolyzed and the G-protein switches itself off and resets. GTP hydrolysis is stimulated by interaction with "GAP (GTPase activating proteins)" or "RGS (regulator of G protein signaling) " proteins. d. Ultimately, the inactive G protein/GDP complex receives a new upstream signal, which induces replacement of inactive GDP with active GTP and repeat
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Lecture 7 2 3. The trimeric G-proteins then typically activate downstream targets by creating an intracellular second messenger , which in turn passes on the signal to other target molecules. 4. Examples of these intracellular secondary messengers include cyclic-AMP (cAMP) and Ca2+. Both stimulatory (G s ) and inhibitory (G i )-protein complexes are known. D. Example of G s action in mediating the effects of adrenaline; step-by-step mechanism: (Adrenaline: a hormone that induces glycogen breakdown in muscle cells - mediated by G proteins and cAMP ) 1. extracellular domain of ß-adrenergic receptor binds adrenaline. 2. receptor interacts with intracellular trimeric G-protein, induces exchange of GTP
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This note was uploaded on 03/02/2010 for the course ECL 242 taught by Professor Holly during the Winter '10 term at UC Davis.

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BIS104 Note7 - Lecture 7 Bio Sci 104 G-protein-coupled...

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