Molecular Identification of High and Low Affinity Receptors for Nicotinic Acid*

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 Gi-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 Gi-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.

[1]  C. Stannek,et al.  G protein-coupled receptor for nicotinic acid in mouse macrophages. , 2002, Biochemical pharmacology.

[2]  K. Pfeffer,et al.  PUMA‐G, an IFN‐γ‐inducible gene in macrophages is a novel member of the seven transmembrane spanning receptor superfamily , 2001, European journal of immunology.

[3]  Jilly F. Evans,et al.  Discovery and mapping of ten novel G protein-coupled receptor genes. , 2001, Gene.

[4]  C. Stannek,et al.  Characterization of a G protein-coupled receptor for nicotinic acid. , 2001, Molecular pharmacology.

[5]  S. Tavintharan,et al.  The benefits of niacin in atherosclerosis , 2001, Current atherosclerosis reports.

[6]  P. Murdock,et al.  Cloning, localisation and functional expression of a novel human, cerebellum specific, two pore domain potassium channel. , 2000, Brain research. Molecular brain research.

[7]  M. Marzioch,et al.  Functional coupling of mammalian receptors to the yeast mating pathway using novel yeast/mammalian G protein α‐subunit chimeras , 2000, Yeast.

[8]  S. Dowell,et al.  A constitutively active G‐protein‐coupled receptor causes mating self‐compatibility in the mushroom Coprinus , 1999, The EMBO journal.

[9]  R. Müller,et al.  Yeast vectors for the controlled expression of heterologous proteins in different genetic backgrounds. , 1995, Gene.

[10]  P. Gazzotti,et al.  Purification and Reconstitution of the Ca2+-Pumping ATPase of Red Blood Cells , 1994 .

[11]  K. Matsushima,et al.  Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors. , 1993, International immunology.

[12]  J. Bradley,et al.  Receptors that couple to 2 classes of G proteins increase cAMP and activate CFTR expressed in Xenopus oocytes. , 1993, Receptors and Channels.

[13]  J. Morrow,et al.  Identification of skin as a major site of prostaglandin D2 release following oral administration of niacin in humans. , 1992, The Journal of investigative dermatology.

[14]  G. Milligan,et al.  Gi down-regulation as a mechanism for heterologous desensitization in adipocytes. , 1992, The Journal of biological chemistry.

[15]  A. L. Goldin.  Maintenance of Xenopus laevis and oocyte injection. , 1992, Methods in enzymology.

[16]  R. Stern,et al.  Tolerance to nicotinic acid flushing , 1991, Clinical pharmacology and therapeutics.

[17]  C. Sirtori,et al.  Plasma lipid lowering activity of acipimox in patients with type II and type IV hyperlipoproteinemia. Results of a multicenter trial. , 1988, Atherosclerosis.

[18]  D. Hunninghake,et al.  Controlled trial of acifran in type II hyperlipoproteinemia , 1985, Clinical pharmacology and therapeutics.

[19]  G. Schultz,et al.  Islet‐activating protein prevents nicotinic acid‐induced GTPase stimulation and GTP but not GTPγS‐induced adenylate cyclase inhibition in rat adipocytes , 1983, FEBS letters.

[20]  G. Schultz,et al.  Inhibition of adenylate cyclase and stimulation of a high affinity GTPase by the antilipolytic agents, nicotinic acid, acipimox and various related compounds. , 1983, Arzneimittel-Forschung.

[21]  M. Cayen,et al.  Evaluation of the lipid-lowering activity of AY-25,712 in rats. , 1982, Atherosclerosis.

[22]  P. Lovisolo,et al.  Pharmacological profile of a new antilipolytic agent: 5-methyl-pyrazine-2-carboxylic acid 4-oxide (acipimox) (1) II - Antilipolytic and blood lipid lowering activity. , 1981, Pharmacological research communications.

[23]  K. Credner,et al.  [Salts of 5-methylpyrazole-3-carboxylic acid with basically substituted adenine derivatives. Identification and lipolysis inhibitory activity (author's transl)]. , 1981, Arzneimittel-Forschung.