REGULATION OF G-PROTEIN FUNCTION - IMPLICATIONS FOR HEART-DISEASE

Heterotrimeric GTP-binding and -hydrolyzing proteins (G proteins) link members of a family of seven-helix transmembrane receptors (G protein -coupled receptors, GPCR) to intracellular effecters. The coupling mec hanism involves the G protein completing a cycle of activation, dissoc iation into a and py subunits, deactivation, and reassociation. At the center of this cycle is the a subunit, in which activation by GPCR, G TPase activity, and regulation of effector are combined. Whereas Ga's functional domains and residues had already been inferred from mutagen esis studies, the recent solution of the crystal structure has elucida ted the structural basis of a subunit function. It is now clear that a n irregularity in any GPCR pathway component could cause a physiologic al defect. This is confirmed by the identification of mutations in GPC R and Ga's in various human diseases. Although several cardiomyopathie s are associated with abnormal GPCR function, mutations are unlikely i n these disorders. The last few years, other aspects of G protein func tion have moved into focus: e.g. posttranslational modifications; effe ctor regulation by py subunits; GTPase activating protein (GAP) activi ty of effecters; G protein expression levels etc. When comparing the r egulation of G protein functional activity in cAMP and in inositol pho sphate generating pathways, an extrapolation can be made to data on th e status of these pathways in some cardiovascular diseases.