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This Article Free via Open Access: OA OA Full Text Full Text (PDF) OA All Versions of this Article: 578/2/425    most recent jphysiol.2006.119479v2 jphysiol.2006.119479v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Smith, M. A. Articles by Ashford, M. L. J. Search for Related Content PubMed PubMed Citation Articles by Smith, M. A. Articles by Ashford, M. L. J. Related Collections Neuroscience

¹ Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
² Centre for Diabetes and Endocrinology, Rayne Institute, University College London, London, UK

The hypothalamic melanocortin system is crucial for the control of appetite and body weight. Two of the five melanocortin receptors, MC3R and MC4R are involved in hypothalamic control of energy homeostasis, with the MC4R having the major influence. It is generally thought that the main impact of the melanocortin system on hypothalamic circuits is external to the arcuate nucleus, and that any effect locally in the arcuate nucleus is inhibitory on proopiomelanocortin-expressing (POMC) neurons. In contrast, using current- and voltage-clamp recordings from identified neurons, we demonstrate that MC3R and MC4R agonists depolarize arcuate POMC neurons and a separate arcuate neuronal population identified by the rat insulin 2 promoter (RIPCre) transgene expression. Furthermore, the endogenous MC3R and MC4R antagonist, agouti-related protein (AgRP), hyperpolarizes POMC and RIPCre neurons in the absence of melanocortin agonist, consistent with inverse agonism at the MC4R. A decreased transient outward (I_A) potassium conductance, and to a lesser extent the inward rectifier (K_IR) conductance, underlies neuronal depolarization, whereas an increase in I_A mediates AgRP-induced hyperpolarization. Accordingly, POMC and RIPCre neurons may be targets for peptide transmitters that are possibly released locally from AgRP-expressing and POMC neurons in the arcuate nucleus, adding further previously unappreciated complexity to the arcuate system.

(Received 17 August 2006; accepted after revision 19 October 2006; first published online 26 October 2006)
Corresponding author M. Ashford: Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK. Email: m.l.j.ashford{at}dundee.ac.uk

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