Serotonin 5-hydroxytryptamine2C receptor signaling in hypothalamic proopiomelanocortin neurons:: Role in energy homeostasis in females

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 17 beta-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 alpha(q) phospholipase C (PLC)-protein kinase C delta-protein kinase A pathway. We hypothesized that the mER and neurotransmitter receptor signaling pathways converge to control energy homeostasis. Because 5-HT2C receptors mediate many of the effects of serotonin in POMC neurons, we elucidated the common signaling pathways of E 2 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-HT2C) and 5-HT2A receptors were coexpressed in POMC neurons. The 5-HT2A/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-HT2C receptor antagonists 8-[5-(2,4-dimethoxy-5-(4-trifluoromethyl-phenylsulphonamido) 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-HT2C receptor was G alpha(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 mu M, and E-2, 50 nM) produced additive effects. Although there was a significant gender difference in the effects of E 2 on baclofen responses, there was no gender difference in 5-HT2C receptor-mediated effects. Finally, both DOI and estrogen (intracerebroventricular) inhibited feeding in ovariectomized female mice. Therefore, the G alpha(q) signaling pathways of the mER and 5-HT2C receptors may converge to enhance synaptic efficacy in brain circuits that are critical for maintaining homeostatic functions.