The receptor revolution--multiplicity of G-protein-coupled receptors.

The superfamily of G-protein-coupled receptors (GPCR) is probably the largest protein-encoding gene family in our genome. It is already known to include hundreds of members and many more are expected to emerge as the molecular cloning revolution proceeds. By definition the GPCR respond to ligands by interacting with intracellular G-proteins and thereby transduce external signals to the interior of the cell. A large body of evidence suggests that the GPCR are organized in the cell membrane like bacteriorhodopsin (BR). All GPCR possess seven hydrophobic membrane-spanning segments which seem to form a characteristic BR-like barrel structure. Thus, the three-dimensional structure of BR may be used as a framework for computer-aided structural modelling of GPCR. The ligands which activate the various members of the GPCR family include an enormous variety of molecules such as amines, amino acids and peptides as well as several small hydrophobic molecules. Many ligands bind to multiple distinct GPCR, e.g. neuropeptide Y (NPY). We have isolated molecular clones encoding a human NPY receptor whose binding properties conform to those of the Y1 subtype. This clone will be a useful tool in our efforts to unravel the molecular mechanisms of the many physiological functions of neuropeptide Y.