O

D. Protein synthesis-regulating receptor

Amino acids

Mode of Operation of G-Protein-Coupled Receptors

Signal transduction at G-protein-cou-pled receptors uses essentially the same basic mechanisms (A). Agonist binding to the receptor leads to a change in receptor protein conformation. This change propagates to the G-protein: the a-subunit exchanges GDP for GTP, then dissociates from the two other subunits, associates with an effector protein, and alters its functional state. The a-subunit slowly hydrolyzes bound GTP to GDP. Ga-GDP has no affinity for the effector protein and reassociates with the p and Y subunits (A). G-proteins can undergo lateral diffusion in the membrane; they are not assigned to individual receptor proteins. However, a relation exists between receptor types and G-protein types (B). Furthermore, the a-subunits of individual G-proteins are distinct in terms of their affinity for different effector proteins, as well as the kind of influence exerted on the effector protein. Ga-GTP of the Gs-protein stimulates adenylate cyclase, whereas Ga-GTP of the Gj-protein is inhibitory. The G-protein-coupled receptor family includes mus-carinic cholinoceptors, adrenoceptors for norepinephrine and epinephrine, receptors for dopamine, histamine, serotonin, glutamate, GABA, morphine, prostaglandins, leukotrienes, and many other mediators and hormones.

Major effector proteins for G-pro-tein-coupled receptors include adenylate cyclase (ATP ^ intracellular messenger cAMP), phospholipase C (phos-phatidylinositol ^ intracellular messengers inositol trisphosphate and di-acylglycerol), as well as ion channel proteins. Numerous cell functions are regulated by cellular cAMP concentration, because cAMP enhances activity of protein kinase A, which catalyzes the transfer of phosphate groups onto functional proteins. Elevation of cAMP levels inter alia leads to relaxation of smooth muscle tonus and enhanced contractility of cardiac muscle, as well as increased glycogenolysis and lipolysis (p.

84). Phosphorylation of cardiac calcium-channel proteins increases the probability of channel opening during membrane depolarization. It should be noted that cAMP is inactivated by phosphodiesterase. Inhibitors of this enzyme elevate intracellular cAMP concentration and elicit effects resembling those of epinephrine.

The receptor protein itself may undergo phosphorylation, with a resultant loss of its ability to activate the associated G-protein. This is one of the mechanisms that contributes to a decrease in sensitivity of a cell during prolonged receptor stimulation by an agonist (desensitization).

Activation of phospholipase C leads to cleavage of the membrane phospho-lipid phosphatidylinositol-4,5 bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 promotes release of Ca2+ from storage organelles, whereby contraction of smooth muscle cells, breakdown of glycogen, or exocy-tosis may be initiated. Diacylglycerol stimulates protein kinase C, which phosphorylates certain serine- or threo-nine-containing enzymes.

The a-subunit of some G-proteins may induce opening of a channel protein. In this manner, K+ channels can be activated (e.g., ACh effect on sinus node, p. 100; opioid action on neural impulse transmission, p. 210).

Protein Operated Channels
A. G-Protein-mediated effect of an agonist
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