title: Molecular identification of high and low affinity receptors for nicotinic acid.
abstract: Nicotinic acid has been used clinically for over 40 years in the treatment of dyslipidemia producing a desirable normalization of a range of cardiovascular risk factors, including a marked elevation of high density lipoprotein and a reduction in mortality. The precise mechanism of action of nicotinic acid is unknown, although it is believed that activation of a G(i)-G protein-coupled receptor may contribute. Utilizing available information on the tissue distribution of nicotinic acid receptors, we identified candidate orphan receptors. The selected orphan receptors were screened for responses to nicotinic acid, in an assay for activation of G(i)-G proteins. Here we describe the identification of the G protein-coupled receptor HM74 as a low affinity receptor for nicotinic acid. We then describe the subsequent identification of HM74A in follow-up bioinformatics searches and demonstrate that it acts as a high affinity receptor for nicotinic acid and other compounds with related pharmacology. The discovery of HM74A as a molecular target for nicotinic acid may facilitate the discovery of superior drug molecules to treat dyslipidemia.
authors.affiliation: Department of 7TMR Systems Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom. alan.x.wise@gsk.com
authors.forename: Alan
authors.initials: A
authors.lastname: Wise
authors.forename: Steven M
authors.initials: SM
authors.lastname: Foord
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Fraser
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Barnes
authors.forename: Nabil
authors.initials: N
authors.lastname: Elshourbagy
authors.forename: Michelle
authors.initials: M
authors.lastname: Eilert
authors.forename: Diane M
authors.initials: DM
authors.lastname: Ignar
authors.forename: Paul R
authors.initials: PR
authors.lastname: Murdock
authors.forename: Klaudia
authors.initials: K
authors.lastname: Steplewski
authors.forename: Andrew
authors.initials: A
authors.lastname: Green
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brown
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dowell
authors.forename: Philip G
authors.initials: PG
authors.lastname: Szekeres
authors.forename: David G
authors.initials: DG
authors.lastname: Hassall
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Marshall
authors.forename: Shelagh
authors.initials: S
authors.lastname: Wilson
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Pike
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D019992:Databases as Topic; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000494:pharmacology; D006801:Humans; D006949:Hyperlipidemias / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D008969:Molecular Sequence Data; D009525:Niacin / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D011485:Protein Binding; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D014981:Xenopus
chemical_list: D018076:DNA, Complementary; D005663:Furans; D000960:Hypolipidemic Agents; D011719:Pyrazines; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D009525:Niacin; C036804:acifran; C027696:acipimox