Serotonin 5-HT 2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons

T. A. Roepke, A. W. Smith, Oline Ronnekleiv, Martin Kelly

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22 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume302
Issue number11
DOIs
StatePublished - Jun 1 2012

Fingerprint

Pro-Opiomelanocortin
Serotonin Receptors
Serotonin
Neurons
Inhibition (Psychology)
Receptor, Serotonin, 5-HT1B
Neuropeptide Y
Feeding Behavior
Transgenic Mice
Fasting
Eating

Keywords

  • Feeding behavior
  • Hypothalamus
  • KCNQ channels

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

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title = "Serotonin 5-HT 2C 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.",
keywords = "Feeding behavior, Hypothalamus, KCNQ channels",
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T1 - Serotonin 5-HT 2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons

AU - Roepke, T. A.

AU - Smith, A. W.

AU - Ronnekleiv, Oline

AU - Kelly, Martin

PY - 2012/6/1

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N2 - 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.

AB - 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.

KW - Feeding behavior

KW - Hypothalamus

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