Characterization of a G Protein-Coupled Receptor for Nicotinic Acid
- Anna Lorenzen1,
- Christina Stannek1,
- Heidrun Lang1,
- Viktor Andrianov2,
- Ivars Kalvinsh2 and
- Ulrich Schwabe1
- 1Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany (A.L., C.S., H.L., U.S.); and 2Department of Medicinal Chemistry, Latvian Institute of Organic Synthesis, Riga, Latvia (V.A., I.K.)
Abstract
Nicotinic acid is a lipid-lowering agent widely used to treat hypertriglyceridemia and to elevate low high density lipoprotein levels. However, the underlying mechanisms are poorly understood. In this study, G protein activation by nicotinic acid and derivatives was assessed as stimulation of guanosine 5′-(γ-[35S]-thio)triphosphate ([35S]GTPγS) binding, and [3H]nicotinic acid was used for specific labeling of binding sites. Nicotinic acid (EC50 ∼1 μM) stimulated [35S]GTPγS binding in membranes from rat adipocytes and spleen, but not from other tissues. G protein activation in adipocyte membranes in the presence of maximally activating concentrations of the selective A1adenosine receptor agonist 2-chloro-N6-cyclopentyladenosine and nicotinic acid was almost additive, indicating that G proteins of mostly distinct pools were activated by these agonists. G protein activation by nicotinic acid and related substances in spleen and adipocytes revealed identical pharmacological profiles. [3H]Nicotinic acid specifically detected guanine nucleotide-sensitive binding sites of identical pharmacology in adipocyte and spleen membranes. The site of action of nicotinic acid is distinct from other G protein-coupled receptors. These data indicate that nicotinic acid most probably acts on a specific G protein-coupled receptor.
Footnotes
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Send reprint requests to: Anna Lorenzen, Pharmakologisches Institut der Universität Heidelberg, Im Neuenheimer Feld 366, D-69120 Heidelberg, Germany. E-mail:anna.lorenzen{at}urz.uni-heidelberg.de
- Abbreviations:
- acipimox
- 5-methylpyrazine-2-carboxylic acid-4-oxide
- CCPA
- 2-chloro-N6-cyclopentyladenosine
- CHAPS
- 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate
- GDPβS
- guanosine 5-(β-thio)diphosphate
- GTPγS
- guanosine 5′-(γ-thio)triphosphate
- UK 14,304
- 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine
- R(+)-WIN 55,212-2 mesylate
- R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate
- R-PIA
- [3H]R-N6-phenylisopropyladenosine
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- Received March 8, 2000.
- Accepted November 2, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
