Novel G-protein-coupled receptor genes expressed in the brain: continued discovery of important therapeutic targets.
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.
Lee
Dennis K
DK
Department of Pharmacology, University of Toronto, Medical Science Building, 8 Taddle Creek Rd. Rm. 4352, Toronto, Ontario M5S 1A8, Canada.
George
Susan R
SR
O'Dowd
Brian F
BF
D000588:Amines / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002491:Central Nervous System Agents / Q000494:pharmacology*; D015195:Drug Design; D020869:Gene Expression Profiling; D006801:Humans; D008024:Ligands; D008322:Mammals / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D018377:Neurotransmitter Agents / Q000502:physiology; D011487:Protein Conformation; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000145:classification / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D012243:Rhodopsin / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000588:Amines; D002491:Central Nervous System Agents; D008024:Ligands; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D043562:Receptors, G-Protein-Coupled; D012243:Rhodopsin