Heptahelical Receptor Signaling: Beyond the G Protein Paradigm

Abstract

Heptahelical receptors, so called because of their conserved structure featuring seven α-helical transmembrane spans, mediate physiological responses to a remarkably diverse array of stimuli. These include hormones, neurotransmitters, small peptides, proteins, lipids and ions, as well as sensory stimuli such as odorants, pheromones, bitter and sweet tastants, and photons. This superfamily of receptors contains >1,000 members, making it the largest class of cell surface molecules in the mammalian genome. Moreover, it was found recently that heptahelical receptors account for >5% of the total genes in the Caenorhabditus elegans genome (Bargmann, 1998), testifying to the importance of this family and demonstrating that the structure of these receptors has been highly conserved throughout evolution. For many years, this family of receptors has been referred to as G protein– coupled, a term based on the well documented paradigm that such receptors interact with and signal through heterotrimeric G proteins. Simply stated, this repeatedly validated paradigm is that when heptahelical receptors are stimulated with ligand, their intracellular regions undergo conformational changes, allowing the receptors to interact with G proteins. This association in turn causes conformational changes in the G proteins that facilitate GDP release and GTP binding, leading to dissociation of Gα and Gβγ subunits. The activated G protein subunits then bind to and regulate various intracellular effectors.

During the past few years, however, several reports have appeared in the literature describing various physiological consequences of heptahelical receptor stimulation that, surprisingly, do not seem to be mediated by G protein activation. Concurrently, novel techniques for detecting protein–protein interactions such as yeast two-hybrid, phage display, and fusion protein overlays have revealed associations of heptahelical receptors with a variety of intracellular partners other than G proteins. This convergence of unexplained physiology and provocative protein– protein interactions has led increasingly to the realization that the mechanisms of heptahelical receptor signaling are more diverse than previously thought. This mini-review summarizes recent work on the subject of intracellular signaling by heptahelical receptors through means other than classical G protein pathways.