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The Journal of Neuroscience, October 22, 2003, 23(29):9529-9540

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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

Classically, 17-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 GABA_B 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 or , suggesting that E₂ acts through a unique membrane receptor. We characterized the coupling of this estrogen receptor to a G_q-mediated activation of phospholipase C, leading to the upregulation of protein kinase C and protein kinase A activity in these neurons. Moreover, using single-cell reverse transcription-PCR, we identified the critical transcripts, PKC and its downstream target adenylyl cyclase VII, for rapid, novel signaling of E₂ in GABA, POMC, and dopamine neurons. Therefore, this unique G_q-coupled estrogen receptor may be involved in rapid signaling in hypothalamic neurons that are critical for normal homeostatic functions.

Key words: GABA_B receptor; GIRK; dopamine; GAD; POMC; SERMs

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Received June 13, 2003; revised August 1, 2003; accepted August 22, 2003.

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