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Melanin-Concentrating Hormone Receptor 1 Activates Extracellular Signal-Regulated Kinase and Synergizes with G_s-Coupled Pathways

Section on Obesity (P.P., D.J.T., E.M.-F.), Research Division, Joslin Diabetes Center, and the Division of Endocrinology (I.T.), Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Eleftheria Maratos-Flier, Research Division, Section on Obesity, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215. E-mail: terry.maratos-flier{at}joslin.harvard.edu.

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 ß-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.

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