Characterization of a G protein-coupled receptor for nicotinic acid.
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'-(gamma-[(35)S]-thio)triphosphate ([(35)S]GTPgammaS) binding, and [(3)H]nicotinic acid was used for specific labeling of binding sites. Nicotinic acid (EC(50) approximately 1 microM) stimulated [(35)S]GTPgammaS 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 A(1) adenosine receptor agonist 2-chloro-N(6)-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. [(3)H]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.
Lorenzen
A
A
Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany. anna.lorenzen@furz.uni-heidelberg.de
Stannek
C
C
Lang
H
H
Andrianov
V
V
Kalvinsh
I
I
Schwabe
U
U
D000067956:Adenylyl Cyclase Inhibitors; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009525:Niacin / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013462:Sulfur Radioisotopes; D014316:Tritium
D000067956:Adenylyl Cyclase Inhibitors; D000960:Hypolipidemic Agents; D011719:Pyrazines; D011956:Receptors, Cell Surface; D011978:Receptors, Nicotinic; D013462:Sulfur Radioisotopes; D014316:Tritium; D009525:Niacin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C027696:acipimox