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J. Neurosci. 23 (29): 9529-9540

Copyright © 2003 by the Society for Neuroscience.


Behavioral/Systems/Cognitive

Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C

Jian Qiu,1 Martha A. Bosch,1 Sandra C. Tobias,2 David K. Grandy,1 Thomas S. Scanlan,2 Oline K. Rønnekleiv,1 , and Martin J. Kelly1

1Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239, and 2Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94143

Abstract: Classically, 17{beta}-estradiol (E2) is thought to control homeostatic functions such as reproduction, stress responses, feeding, sleep cycles, temperature regulation, and motivated behaviors through transcriptional events. Although it is increasingly evident that E2 can also rapidly activate kinase pathways to have multiple downstream actions in CNS neurons, the receptor(s) and the signal transduction pathways involved have not been identified. We discovered that E2 can alter µ-opioid and GABA neurotransmission rapidly through nontranscriptional events in hypothalamic GABA, proopiomelanocortin (POMC), and dopamine neurons. Therefore, we examined the effects of E2 in these neurons using whole-cell recording techniques in ovariectomized female guinea pigs. E2 reduced rapidly the potency of the GABAB receptor agonist baclofen to activate G-protein-coupled, inwardly rectifying K+ channels in hypothalamic neurons. These effects were mimicked by the membrane impermeant E2-BSA and selective estrogen receptor modulators, including a new diphenylacrylamide compound, STX, that does not bind to intracellular estrogen receptors {alpha} or {beta}, suggesting that E2 acts through a unique membrane receptor. We characterized the coupling of this estrogen receptor to a G{alpha}q-mediated activation of phospholipase C, leading to the upregulation of protein kinase C{delta} and protein kinase A activity in these neurons. Moreover, using single-cell reverse transcription-PCR, we identified the critical transcripts, PKC{delta} and its downstream target adenylyl cyclase VII, for rapid, novel signaling of E2 in GABA, POMC, and dopamine neurons. Therefore, this unique Gq-coupled estrogen receptor may be involved in rapid signaling in hypothalamic neurons that are critical for normal homeostatic functions.

Key Words: GABAB receptorGIRKdopamineGADPOMCSERMs


Received for publication June 13, 2003. Revision received August 1, 2003. Accepted for publication August 22, 2003.


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