title: Serotonin 5-HT2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons.
abstract: Hypothalamic proopiomelanocortin (POMC) neurons are controlled by many central signals, including serotonin. Serotonin increases POMC activity and reduces feeding behavior via serotonion [5-hydroxytryptamine (5-HT)] receptors by modulating K(+) currents. A potential K(+) current is the M-current, a noninactivating, subthreshold outward K(+) current. Previously, we found that M-current activity was highly reduced in fasted vs. fed states in neuropeptide Y neurons. Because POMC neurons also respond to energy states, we hypothesized that fasting may alter the M-current and/or its modulation by serotonergic input to POMC neurons. Using visualized-patch recording in neurons from fed male enhanced green fluorescent protein-POMC transgenic mice, we established that POMC neurons expressed a robust M-current (102.1 ± 6.7 pA) that was antagonized by the selective KCNQ channel blocker XE-991 (40 μM). However, the XE-991-sensitive current in POMC neurons did not differ between fed and fasted states. To determine if serotonin suppresses the M-current via the 5-HT(2C) receptor, we examined the effects of the 5-HT(2A)/5-HT(2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) on the M-current. Indeed, DOI attenuated the M-current by 34.5 ± 6.9% and 42.0 ± 5.3% in POMC neurons from fed and fasted male mice, respectively. In addition, the 5-HT(1B)/5-HT(2C) receptor agonist m-chlorophenylpiperazine attenuated the M-current by 42.4 ± 5.4% in POMC neurons from fed male mice. Moreover, the selective 5-HT(2C) receptor antagonist RS-102221 abrogated the actions of DOI in suppressing the M-current. Collectively, these data suggest that although M-current expression does not differ between fed and fasted states in POMC neurons, serotonin inhibits the M-current via activation of 5-HT(2C) receptors to increase POMC neuronal excitability and, subsequently, reduce food intake.
authors.affiliation: Dept. of Physiology & Pharmacology,Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Roepke
authors.forename: A W
authors.initials: AW
authors.lastname: Smith
authors.forename: O K
authors.initials: OK
authors.lastname: Rønnekleiv
authors.forename: M J
authors.initials: MJ
authors.lastname: Kelly
mesh_terms: D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D005215:Fasting / Q000502:physiology; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000502:physiology*; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; C107821:8-(5-(5-amino-2,4-dimethoxyphenyl)-5-oxopentyl)-1,3,8-triazaspiro(4.5)decane-2,4-dione; D000662:Amphetamines; D000873:Anthracenes; D002121:Calcium Channel Blockers; D051656:KCNQ Potassium Channels; D010879:Piperazines; D026902:Potassium Channel Blockers; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; D013449:Sulfonamides; D011333:Pro-Opiomelanocortin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C015068:1-(3-chlorophenyl)piperazine