The G protein-coupled, or seven membrane-spanning, receptors (GPCRs)
constitute the largest and most diverse superfamily of cell surface receptors in
the mammalian genome. Approximately 800 distinct genes encoding functional
GPCRs make up greater than 1% of the human genome (1,2). With alternative
splicing, it is estimated that 1000 to 2000 discrete receptor proteins may be
4 Luttrell
expressed. In nematodes, the situation is even more dramatic. In
Caenorhabditis elegans, genes encoding more than 1000 GPCRs comprise 5%
of the genome (3). Such evolutionary diversity generates GPCRs that detect an
extraordinary array of extracellular stimuli, from neurotransmitters and peptide
hormones to odorants and photons of light. Humans literally see, smell,
and taste the world through GPCRs. Internally, GPCRs function in neurotransmission,
direct neuroendocrine control of physiological homeostasis and reproduction,
regulate hemodynamics and intermediary metabolism, and influence
the growth, proliferation, differentiation, and death of multiple cell types. Not
surprisingly then, it is estimated that more than half of all drugs in current
clinical use target GPCRs, acting either to mimic endogenous GPCR ligands,
to block ligand access to the receptor, or to modulate ligand production (4).