Serotonin 5-Hydroxytryptamine2C Receptor Signaling in Hypothalamic Proopiomelanocortin Neurons: Role in Energy Homeostasis in Females

Abstract

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␤-estradiol (E 2 ) 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 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. 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 EC 50 concentrations (DOI, 20 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-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.The hypothalamus is a key central nervous system center for controlling many homeostatic processes, and hypothalamic POMC neurons are critical neurons in these hypothalamic circuits (Elmquist et al., 1999;Cone, 2005;Gropp et al.,

Membrane-initiated estrogen signaling in hypothalamic neurons

“…The positive modulation of CREB activity occurs via ER interactions with metabotropic glutamate receptors 1(mGluR 1) and the negative modulation via mGluR 2/3 ( Figure 1A). The type of interaction, however, is currently unknown, but potentially could be similar to that described for mER and 5HT 2C receptors which have diverse but convergent signaling pathways in arcuate neurons (Qiu et al, 2007). A similar scenario has been hypothesized for the rapid E2-induced activation of μ-opioid receptors in the medial preoptic area associated with female sex behavior (Dewing et al, 2007).…”

Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

“…In other words, interaction with the HTR2A/2C receptors is associated with a desensitization of the HTR1A receptors, a mechanism that has been proposed to underline the antidepressant efficacy of the serotonergic drugs [Hensler, 2003]. Consistently, Barabanova and coworkers demonstrated that the use of ketanserin (a 5-HT(2A/2C) receptor antagonist) had antidepressant activity in animal models and, of note, c-fos expression was enhanced by this treatment specifically in the in the paraventricular nucleus of hypothalamus [Barabanova et al, 2007;Qiu et al, 2007]. Heisler et al [2007a] recently reported that the chronic activation of the HPA axis, a frequent characteristic of depressive episodes, is dependent on the HTR2C activity, which characterizes the oxitocin and vasopressin producing neurons in the hypothalamic paraventral nucleus as well [Ho et al, 2007].…”

Insights into 5-HT2C Receptor Function Gained from Transgenic Mouse Models

“…Studies of mutant mice with functional alterations of 5-HT 2C R activity have elucidated some of the mechanisms underlying this important regulation. In the hypothalamus, 5-HT 2C Rs are prominently expressed on POMCcontaining neurons of the ventrolateral arcuate nucleus (Wright et al 1995;Pasqualetti et al 1999;Heisler et al 2002), and serotonin binding to these receptors is thought to contribute to neuronal activation (Qiu et al 2007). POMC neurons in the arcuate are also activated by leptin signaling through the leptin receptor (Cheung et al 1997;Elias et al 1999;Cowley et al 2001) and serotonin signaling through the 5-HT 1B receptor (Ho et al 2007;Nonogaki et al 2007).…”