Involvement of the βγ subunits of G proteins in the cAMP response induced by stimulation of the histamine H1 receptor.
Stimulation of the histamine H1 receptor has been shown to enhance adenosine 3', 5'-cyclic monophosphate (cAMP) accumulation in various cell types but, to date, the mechanism by which this occurs is still unclear. In the present study, we examined the possibility that the betagamma subunits of G proteins (G betagamma) are involved in this process in cultured Chinese hamster ovary cells transfected with the human histamine H1 receptor (CHO-H1). Histamine increased intracellular cAMP levels in a concentration-dependent manner in CHO-H1 cells, and this histamine action was abolished by pyrilamine (1 microM). Inhibition of histamine H1 receptor-G(q) protein coupling by stable expression of the C-terminal peptide of G alpha(q) protein significantly attenuated the cAMP accumulation induced by histamine. By comparison, neither BAPTA/AM (50 microM), an intracellular Ca2+ chelator, nor GF 109203X (1 microM), an inhibitor of protein kinase C, influenced the cAMP response. Histamine H1 receptor-mediated cAMP accumulation was significantly inhibited by transient transfection of CHO-H1 cells with the C-terminal peptide of beta-adrenoceptor kinase I (residues 542-685), a scavenger of G betagamma. Stable expression of the C-terminal peptide of the G alpha(s) protein, but not treatment with pertussis toxin (200 ng/ml for 24 h), attenuated the histamine H1 receptor-mediated cAMP accumulation. These results suggest that stimulation of histamine H1 receptors activates adenylyl cyclase through the release of G betagamma subunits from G proteins, thereby elevating intracellular cAMP levels.
Maruko
Takeshi
T
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Nakahara
Tsutomu
T
Sakamoto
Kenji
K
Saito
Maki
M
Sugimoto
Naotoshi
N
Takuwa
Yoh
Y
Ishii
Kunio
K
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D011738:Pyrilamine / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D051552:beta-Adrenergic Receptor Kinases / Q000235:genetics / Q000378:metabolism
C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D007295:Inositol Phosphates; D011969:Receptors, Histamine H1; D006632:Histamine; D000242:Cyclic AMP; D051552:beta-Adrenergic Receptor Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D011738:Pyrilamine