Dennis K Lee

We report the isolation of a cDNA clone named GPR54, which encodes a novel G protein-coupled receptor (GPCR). A PCR search of rat brain cDNA retrieved a clone partially encoding a GPCR. In a library screening this clone was used to isolate a cDNA with an open reading frame (ORF) encoding a receptor of 396 amino acids long which shared significant identities in the transmembrane regions with rat galanin receptors GalR1 (45%), GalR3 (45%) and GalR2 (44%). Northern blot and in situ hybridization analyses revealed that GPR54 is expressed in brain regions (pons, midbrain, thalamus, hypothalamus, hippocampus, amygdala, cortex, frontal cortex, and striatum) as well as peripheral regions (liver and intestine). In COS cell expression of GPR54 no specific binding was observed for 125I-galanin. A recent BLAST search with the rat GPR54 ORF nucleotide sequence recovered the human orthologue of GPR54 in a 3.5 Mb contig localized to chromosome 19p13.3.

The rhodopsin family of G-protein-coupled receptors (GPCRs) is the largest known group of cell-surface mediators of signal transduction. The vast majority of these receptors were discovered by methods based upon shared sequence homologies found throughout this family. While such efforts identified a multitude of receptor subtypes for previously known ligands, numerous receptors have been discovered for which endogenous ligands were unknown. These receptors are commonly referred to as orphan receptors. One of the most important tasks of modern pharmacology lies in elucidating the functions of these receptors. Of particular interest are receptors with recognised expression in the central nervous system, given that many psychiatric and neurodegenerative disorders are mediated by unknown mechanisms. Hence, this collection of putative neurotransmitter and neuromodulator signal mediators represents a substantial and untapped resource for novel drug discovery. Recently, various methodologies have accelerated the discovery of novel ligands for these orphan receptors, identifying the basic components required for further physiological ligand/receptor system characterisation. Equipped with proven ligand identification strategies, the characterisation of all orphan GPCRs and the exploitation of their exciting potential as targets for the discovery of novel drugs is anticipated.