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Molecular and Cellular Biology, February 2003, p. 1054-1060, Vol. 23, No. 3
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.3.1054-1060.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Targeted Disruption of the Mouse Mel1b Melatonin Receptor

Xiaowei Jin,1,{dagger} Charlotte von Gall,2,3,{ddagger} Rick L. Pieschl,4 Valentin K. Gribkoff,4 Jorg H. Stehle,2 Steven M. Reppert,1,3,{ddagger} and David R. Weaver1,3,{ddagger}*

Laboratory of Developmental Chronobiology, MassGeneral Hospital for Children, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114,1 Anatomisches Institut II, Johann Wolfgang Goethe-Universität Frankfurt, D-60590 Frankfurt, Germany,2 Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605,3 Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 064924

Received 29 August 2002/ Returned for modification 16 October 2002/ Accepted 7 November 2002

Two high-affinity, G protein-coupled melatonin receptor subtypes have been identified in mammals. Targeted disruption of the Mel1a melatonin receptor prevents some, but not all, responses to the hormone, suggesting functional redundancy among receptor subtypes (Liu et al., Neuron 19:91-102, 1997). In the present work, the mouse Mel1b melatonin receptor cDNA was isolated and characterized, and the gene has been disrupted. The cDNA encodes a receptor with high affinity for melatonin and a pharmacological profile consistent with its assignment as encoding a melatonin receptor. Mice with targeted disruption of the Mel1b receptor have no obvious circadian phenotype. Melatonin suppressed multiunit electrical activity in the suprachiasmatic nucleus (SCN) in Mel1b receptor-deficient mice as effectively as in wild-type controls. The neuropeptide, pituitary adenylyl cyclase activating peptide, increases the level of phosphorylated cyclic AMP response element binding protein (CREB) in SCN slices, and melatonin reduces this effect. The Mel1a receptor subtype mediates this inhibitory response at moderate ligand concentrations (1 nM). A residual response apparent in Mel1a receptor-deficient C3H mice at higher melatonin concentrations (100 nM) is absent in Mel1a-Mel1b double-mutant mice, indicating that the Mel1b receptor mediates this effect of melatonin. These data indicate that there is a limited functional redundancy between the receptor subtypes in the SCN. Mice with targeted disruption of melatonin receptor subtypes will allow molecular dissection of other melatonin receptor-mediated responses.

* Corresponding author. Present address: Department of Neurobiology, Lazare Research Building, Room 723, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605-2324. Phone: (508) 856-2495. Fax: (508) 856-6266. E-mail: david.weaver{at}umassmed.edu.

{dagger} Present address: CombinatoRx Inc., Boston, MA 02118.

{ddagger} Present address: Department of Neurobiology, University of Massachusetts Medical School, Worcester MA 01605-2324.

Molecular and Cellular Biology, February 2003, p. 1054-1060, Vol. 23, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.3.1054-1060.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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