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The Journal of Neuroscience, May 24, 2006, 26(21):5649-5655; doi:10.1523/JNEUROSCI.0327-06.2006
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Brief Communications
A G-Protein-Coupled Estrogen Receptor Is Involved in Hypothalamic Control of Energy Homeostasis
Jian Qiu,1
Martha A. Bosch,1
Sandra C. Tobias,3
Andree Krust,5
Sharon M. Graham,2
Stephanie J. Murphy,2
Kenneth S. Korach,4
Pierre Chambon,5
Thomas S. Scanlan,3
Oline K. Rønnekleiv,1 and
Martin J. Kelly1
Departments of 1Physiology and Pharmacology and 2Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon 97239-3098, 3Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California 94143, 4Laboratory of Reproductive and Developmental Toxicology, National Institutes of Health, Research Triangle Park, North Carolina 27709, and 5Institute de Genetique et de Biologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique /Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, College de France, 67404 Illkirch-Cedex, France
Correspondence should be addressed to either Dr. Martin J. Kelly or Dr. Oline K. Rønnekleiv, Department of Physiology and Pharmacology, L334, Oregon Health and Science University, Portland, OR 97239-3098. Email: kellym{at}ohsu.edu or ronnekle{at}ohsu.edu
Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation, and motivated behaviors. The critical role of 17 -estradiol (E2) is evident in hypoestrogenic states (e.g., postmenopause) in which many of these functions go awry. The actions of E2 in the brain have been attributed to the activation of estrogen receptors  and through nuclear, cytoplasmic, or membrane actions. However, we have identified a putative membrane-associated estrogen receptor that is coupled to desensitization of GABAB and µ-opioid receptors in guinea pig and mouse hypothalamic proopiomelanocortin neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the Gq-coupled phospholipase C–protein kinase C–protein kinase A pathway, and have established that STX is more potent than E2 in mediating this desensitization in an ICI 182, 780-sensitive manner in both guinea pig and mouse neurons. Both E2 and STX were fully efficacious in estrogen receptor , knock-out mice. Moreover, in vivo treatment with STX, similar to E2, attenuated the weight gain in hypoestrogenic female guinea pigs. Therefore, this membrane-delimited signaling pathway plays a critical role in the control of energy homeostasis and may provide a novel therapeutic target for treatment of postmenopausal symptoms and eating disorders in females.
Key words: GPCR; body weight; GABAB receptor; intracellular signaling; potassium channels; POMC neurons
Received Jan. 24, 2006;
revised April 12, 2006;
accepted April 14, 2006.
Correspondence should be addressed to either Dr. Martin J. Kelly or Dr. Oline K. Rønnekleiv, Department of Physiology and Pharmacology, L334, Oregon Health and Science University, Portland, OR 97239-3098. Email: kellym{at}ohsu.edu or ronnekle{at}ohsu.edu
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