Melanin-concentrating hormone receptor 1 activates extracellular signal-regulated kinase and synergizes with G(s)-coupled pathways.
Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that plays a key role in energy homeostasis. Like many neuropeptides, it signals through two G protein-coupled receptors. MCH receptor 1 (MCHR1) is the sole receptor expressed in rodents and couples to G(i) and G(q) proteins. Little is known about the intracellular pathways engaged by MCH and its receptor. Using HEK293 cells stably expressing MCHR1, we demonstrate that MCH, acting through MCHR1, antagonizes the action of forskolin, an adenylate cyclase activator that increases intracellular levels of cAMP. MCH also inhibits cAMP induction by the G(s)-coupled beta-adrenergic receptor. Activation of either the G(i)- or G(s)-dependent pathway typically results in ERK phosphorylation in HEK293 cells. In contrast to opposing actions on cAMP synthesis, simultaneous MCH and forskolin treatment results in synergistic activation of ERK. This synergy proceeds through pertussis toxin-independent pathways and requires several enzymatic activities such as protein kinase A, protein kinase C, phospholipase C, and Src kinase. Finally, we provide evidence that such positive interactions are not limited to cell lines but can also be observed in the brain.
Pissios
Pavlos
P
Section on Obesity, Research Division, Joslin Diabetes Center, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Trombly
Daniel J
DJ
Tzameli
Iphigenia
I
Maratos-Flier
Eleftheria
E
D000818:Animals; D001921:Brain / Q000201:enzymology; D002460:Cell Line; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004357:Drug Synergism; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D007028:Hypothalamic Hormones / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007668:Kidney; D008543:Melanins / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D010907:Pituitary Hormones / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D011979:Receptors, Pituitary Hormone / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D007028:Hypothalamic Hormones; D008543:Melanins; D010907:Pituitary Hormones; D011943:Receptors, Adrenergic, beta; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor; D005576:Colforsin; C019463:melanin-concentrating hormone; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D019205:GTP-Binding Protein alpha Subunits, Gs; D007545:Isoproterenol