Orphan G-protein-coupled receptors and natural ligand discovery

Catalog of 300 SNPs in 23 genes encoding G-protein coupled receptors

“…So far, a large number of studies have reported genetic variations of G-protein coupled receptor gene loci and their role in etiology or predisposition of human diseases (Rana et al 2001). G-protein coupled receptors are also considered to be good potential targets for drug development (Howard et al 2001). To expand the genetic basis for drug development as well as eventually to enable clinicians to predict efficacy and adverse drug reactions, we explored SNPs among 23 genes encoding G-protein coupled receptors.…”

“…G-protein coupled receptors are cell-surface proteins and are responsible for the signal transduction for a variety of extracellular chemical signals such as photons, Ca 2+ , nucleotides, amino acids, peptides, amines, fatty derivatives, and various polypeptide ligands (see a review by Howard et al 2001). On recognition of such ligands, these proteins mediate a variety of intracellular signals via activation of heterotrimeric G-proteins that in turn, activate various effector proteins, consequently to the left-most column of Table 1).…”

Extension of Drosophila melanogaster life span with a GPCR peptide inhibitor

“…Because of their participation in numerous cell processes, GPCRs are the targets of approximately half of marketed drugs, and new GPCR ligands continue to be pursued and developed 6 . Naïve approaches toward GPCR ligand identification typically involve highthroughput screening of a molecular library (10 2 to 10 5 unique members) in functional, cellbased assays [6][7][8] .…”

“…Naïve approaches toward GPCR ligand identification typically involve highthroughput screening of a molecular library (10 2 to 10 5 unique members) in functional, cellbased assays [6][7][8] . A powerful, alternative approach for the rapid isolation of novel ligands is in vitro peptide selection using mRNA display, which allows access to very high library complexities (>10 13 ) in a robust format 4 .…”

“…Flies constitutively expressing a Mth antagonist peptide exhibit a robust lifespan extension, suggesting that the peptides inhibit Mth signaling in vivo. Our work thus provides novel lifespan-extending ligands for a metazoan and a general approach for the design of modulators of this important class of GPCRs.Because of their participation in numerous cell processes, GPCRs are the targets of approximately half of marketed drugs, and new GPCR ligands continue to be pursued and developed 6 . Naïve approaches toward GPCR ligand identification typically involve highthroughput screening of a molecular library (10 2 to 10 5 unique members) in functional, cellbased assays [6][7][8] .…”