Molecular identification of nicotinic acid receptor.
Nicotinic acid and its derivative, Acipimox, have been widely used in the treatment of hyperlipidemia. Pharmacological studies have demonstrated that they exert the beneficial effect through the activation of a Gi-protein-coupled receptor on adipocyte, which has remained elusive to date. Here we show that a novel GPCR, designated HM74b because of its high similarity to HM74, is a receptor for nicotinic acid. HM74b mRNA is found in human, murine, and rat adipose tissues. Nicotinic acid and Acipimox inhibit forskolin-stimulated intracellular cAMP accumulation in human HM74b-expressing cells and activate GTP gamma S binding in a dose-dependent manner. [3H]Nicotinic acid specifically binds to HM74b-expressing membrane and its binding is replaced by Acipimox. This finding will open a new phase of research on the physiological role of nicotinic acid and will be a clue to develop novel antihyperlipidemic drugs.
Soga
Takatoshi
T
Molecular Medicine Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Kamohara
Masazumi
M
Takasaki
Jun
J
Matsumoto
Shun-ichiro
S
Saito
Tetsu
T
Ohishi
Takahide
T
Hiyama
Hideki
H
Matsuo
Ayako
A
Matsushime
Hitoshi
H
Furuichi
Kiyoshi
K
D017667:Adipocytes / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009525:Niacin / Q000494:pharmacology; D016366:Open Reading Frames; D011061:Poly A; D011719:Pyrazines / Q000737:chemistry*; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution
D018076:DNA, Complementary; D011719:Pyrazines; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D005576:Colforsin; D011061:Poly A; D009525:Niacin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP; C027696:acipimox