G protein-coupled mechanisms and nervous signaling

Bertil Hille Department of Physiology and Biophysics University of Washington Seattle, Washington, 98195 Signaling systems using receptors coupled to GTP- binding regulatory proteins (C proteins) are an essen- tial component of animal nervous systems. We know of hundredsof homologous receptorsand manyintra- cellular biochemical cascades that they control. This review considers the significance for nervous signal- ing of this diversity and of the branching intracellular events set in motion. Many of these questions have been reviewed before (Ross, 1989). My intention, how- ever, is to describe how molecular aspects of this sys- tem may bear on the neuroanatomy and integrative functions of the nervous system. Signaling via a Cascade The first G protein-coupled signaling pathway to be understood in any depth was the 8-adrenergic path- way, which leads to CAMP-dependent phosphoryla- tion of many target proteins. All the molecules car- rying the signal have been identified, purified, and sequenced. The canonical pathway starts with three membrane proteins (Figure IA): the B-adrenergic receptor (an integral membrane protein), the GTP- binding regulatory protein C, (a membrane-associ- ated protein), and a primary effector, the enzyme ade- nylyl cyclase (another integral protein). Binding of the extracellular agonist turns the intracellular face of the receptor into a catalyst that can dock with G, and promote the exchange of cytoplasmic GTP for the GDP normally bound to G, at rest. The unstimulated C&GDP is a stable heterotrimer,