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Serotonin 5-Hydroxytryptamine_2C Receptor Signaling in Hypothalamic Proopiomelanocortin Neurons: Role in Energy Homeostasis in Females

Department of Physiology and Pharmacology (J.Q., C.X., M.A.B., O.K.R., M.J.K.), Department of Anesthesiology and Perioperative Medicine (O.K.R.), Center for the Study of Weight Regulation and Associated Disorders (J.G.M., W.F.), Division of Neuroscience, Oregon National Primate Research Center (M.A.B., O.K.R.), Oregon Health & Science University, Portland, Oregon

Hypothalamic proopiomelanocortin (POMC) neurons play a critical role in the regulation of energy balance, and there is a convergence of critical synaptic input including GABA and serotonin on POMC neurons to regulate their output. We found previously that 17β-estradiol (E₂) reduced the potency of the GABA_B receptor agonist baclofen to activate G protein-coupled inwardly rectifying potassium (GIRK) channels in hypothalamic POMC neurons through a membrane estrogen receptor (mER) via a G_q phospholipase C (PLC)-protein kinase C-protein kinase A pathway. We hypothesized that the mER and neurotransmitter receptor signaling pathways converge to control energy homeostasis. Because 5-HT_2C receptors mediate many of the effects of serotonin in POMC neurons, we elucidated the common signaling pathways of E₂ and 5-HT in guinea pigs using single-cell reverse transcription-polymerase chain reaction (RT-PCR), real time RT-PCR, and whole-cell patch recording. Both 5-hydroxytryptamine_2C (5-HT_2C) and 5-HT_2A receptors were coexpressed in POMC neurons. The 5-HT_2A/C agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) desensitized the GABA_B response in a dose-dependent manner, which was antagonized by the selective 5-HT_2C receptor antagonists 8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulphonamido) phenyl-5-oxopentyl]1,3,8-triazaspiro[4.5] decane-2,4-dione hydrochloride (RS102221) and 1,2,3, 4,10,14b-hexahydro-2-methyldibenzo [c,f]pyrazino[1,2-a]-azepine hydrochloride (ORG 3363). The 5-HT_2C receptor was G_q-coupled to PLC activation and hydrolysis of plasma membrane phosphatidylinositol bisphosphate to directly inhibit GIRK channel activity. Coapplication of the two agonists at their EC₅₀ concentrations (DOI, 20 µM, and E₂, 50 nM) produced additive effects. Although there was a significant gender difference in the effects of E₂ on baclofen responses, there was no gender difference in 5-HT_2C receptor-mediated effects. Finally, both DOI and estrogen (intracerebroventricular) inhibited feeding in ovariectomized female mice. Therefore, the G_q signaling pathways of the mER and 5-HT_2C receptors may converge to enhance synaptic efficacy in brain circuits that are critical for maintaining homeostatic functions.

Address correspondence to: Dr. Jian Qiu, Department of Physiology and Pharmacology, L334, Oregon Health and Science University, Portland, OR 97239-3098. E-mail: qiuj{at}ohsu.edu

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