The complex regulation of receptor-coupled G-proteins

Abstract

Heterotrimeric G-proteins are associated with the cytoplasmic surface of the cell membrane as oligomeric structures. The oligomeric structures were deduced from a variety of studies including target (irradiation) analysis, hydrodynamic evaluation of detergent extracted material, and cross-linking of G-proteins in their membrane environment. From the functional mass determined by target analysis, it was estimated that one receptor (for glucagon) is associated with 8-10 units of Gs, the heterotrimeric G-protein that stimulates adenylyl cyclase. It is proposed that the receptor associates with each monomer of the chain via weak and strong binding forces that are dictated according to whether either GTP or GDP is bound to the alpha-subunits (weak forces) or, due to the hormone-induced release of the nucleotides during the exchange reaction, these subunits become transiently devoid of nucleotides (strong forces). The hormone-induced changes in type and degree of nucleotide binding allow for movement of the receptor along the oligomeric chain and filling of the nucleotide binding sites with the activating nucleotide, GTP. In this manner, the receptor catalytically activates Gs. It is suggested that the dynamic instability of the oligomeric chain produced by the asymmetric distribution of GTP and GDP along the chain results in release of a GTP-monomer from one end and association of a GDP-monomer at the opposite end. Adenylyl cyclase associates with the released GTP-monomer inducing a transient state of the coupled proteins. In a Mg-dependent fashion, hydrolysis of GTP occurs resulting in re-organization of the coupled proteins such that alpha and beta gamma interact with distinct domains of the cyclase molecule. The final state of the coupled process determines the degree of cyclase activity. Release of Pi from its binding site restores association of alpha and beta gamma to the GDP-bound form of the heterotrimer. The latter associates with the oligomeric structure of G-proteins to complete the cycle of events in the overall process of hormonal activation of the system.