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Molecular Endocrinology 13 (12): 2025-2038
Copyright © 1999 by The Endocrine Society

Dual Signaling of Human Mel1a Melatonin Receptors via Gi2, Gi3, and Gq/11 Proteins

Lena Brydon, Florian Roka, Laurence Petit, Pierre de Coppet, Michèle Tissot, Perry Barrett, Peter J. Morgan, Christian Nanoff, A. Donny Strosberg and Ralf Jockers

CNRS-UPR 0415 and Université Paris VII (L.B., L.P., P.D., A.D.S., R.J.) Institut Cochin de Génétique Moléculaire F-75014 Paris, France Institute of Pharmacology (F.R., C.N.) Vienna University A-1090 Vienna, Austria
CNRS-UPRES-A8068 (M.T.) Institut Cochin de Génétique Moleculaire Pavillion Gustave Roussy 75679 Paris Cedex 14, France Rowett Research Institute (L.B., P.B., P.J.M.) Bucksburn, Aberdeen AB2 9SB, United Kingdom

Mel 1a melatonin receptors belong to the superfamily of guanine nucleotide-binding regulatory protein (G protein)-coupled receptors. So far, interest in Mel 1a receptor signaling has focused mainly on the modulation of the adenylyl cyclase pathway via pertussis toxin (PTX)-sensitive G proteins. To further investigate signaling of the human Mel 1a receptor, we have developed an antibody directed against the C terminus of this receptor. This antibody detected the Mel 1a receptor as a protein with an apparent molecular mass of approximately 60 kDa in immunoblots after separation by SDS-PAGE. It also specifically precipitated the 2-[125I]iodomelatonin (125I-Mel)-labeled receptor from Mel 1a-transfected HEK 293 cells. Coprecipitation experiments showed that Gi2, Gi3, and Gq/11 proteins couple to the Mel 1a receptor in an agonist-dependent and guanine nucleotide-sensitive manner. Coupling was selective since other G proteins present in HEK 293 cells, (Gi1, Go, Gs, Gz, and G12) were not detected in receptor complexes. Coupling of the Mel 1a receptor to Gi and Gq was confirmed by inhibition of high-affinity 125I-Mel binding to receptors with subtype-selective G protein {alpha}-subunit antibodies. Gi2 and/or Gi3 mediated adenylyl cyclase inhibition while Gq/11 induced a transient elevation in cytosolic calcium concentrations in HEK 293 cells stably expressing Mel 1a receptors. Melatonin-induced cytosolic calcium mobilization via PTX-insensitive G proteins was confirmed in primary cultures of ovine pars tuberalis cells endogenously expressing Mel 1a receptors. In conclusion, we report the development of the first antibody recognizing the cloned human Mel 1a melatonin receptor protein. We show that Mel 1a receptors functionally couple to both PTX-sensitive and PTX-insensitive G proteins. The previously unknown signaling of Mel 1a receptors through Gq/11 widens the spectrum of potential targets for melatonin.




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