Novel GPCRs and their endogenous ligands: expanding the boundaries of physiology and pharmacology

Nearly all molecules known to signal cells via G proteins have been assigne d a cloned G-protein-coupled-receptor (GPCR) gene. This has been the result of a decade-long genetic search that has also identified some receptors fo r which ligands are unknown; these receptors are described as orphans (oGPC Rs). More than 80 of these novel receptor systems have been identified and the emphasis has shifted to searching for novel signalling molecules. Thus, multiple neurotransmitter systems have eluded pharmacological detection by conventional means and the tremendous physiological implications and poten tial for these novel systems as targets for drug discovery remains unexploi ted. The discovery of all the GPCR genes in the genome and the identificati on of the unsolved receptar-transmitter systems, by determining the endogen ous ligands, represents one of the most important tasks in modern pharmacol ogy.