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Insulin Reduces Neuronal Excitability by Turning on GABA(A) Channels that Generate Tonic Current

Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (γ-aminobutyric acid) decreases neuronal excitability by activating GABA(A) channels that generate phasic and tonic currents. The level of tonic inhibition in ne...

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Autores principales: Jin, Zhe, Jin, Yang, Kumar-Mendu, Suresh, Degerman, Eva, Groop, Leif, Birnir, Bryndis
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021545/
https://www.ncbi.nlm.nih.gov/pubmed/21264261
http://dx.doi.org/10.1371/journal.pone.0016188
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author Jin, Zhe
Jin, Yang
Kumar-Mendu, Suresh
Degerman, Eva
Groop, Leif
Birnir, Bryndis
author_facet Jin, Zhe
Jin, Yang
Kumar-Mendu, Suresh
Degerman, Eva
Groop, Leif
Birnir, Bryndis
author_sort Jin, Zhe
collection PubMed
description Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (γ-aminobutyric acid) decreases neuronal excitability by activating GABA(A) channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. In the hippocampus, interneurons and dentate gyrus granule cells normally have significant tonic currents under basal conditions in contrast to the CA1 pyramidal neurons where it is minimal. Here we show in acute rat hippocamal slices that insulin (1 nM) “turns on” new extrasynaptic GABA(A) channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The channels are activated by more than million times lower GABA concentrations than synaptic channels, generate tonic currents and show outward rectification. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC(50)) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA. They are inhibited by GABA(A) antagonists but have novel pharmacology as the benzodiazepine flumazenil and zolpidem are inverse agonists. The results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed and demonstrate an unexpected hormonal control of the inhibitory channel subtypes and excitability of hippocampal neurons. The insulin-induced new channels provide a specific target for rescuing cognition in health and disease.
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spelling pubmed-30215452011-01-24 Insulin Reduces Neuronal Excitability by Turning on GABA(A) Channels that Generate Tonic Current Jin, Zhe Jin, Yang Kumar-Mendu, Suresh Degerman, Eva Groop, Leif Birnir, Bryndis PLoS One Research Article Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (γ-aminobutyric acid) decreases neuronal excitability by activating GABA(A) channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. In the hippocampus, interneurons and dentate gyrus granule cells normally have significant tonic currents under basal conditions in contrast to the CA1 pyramidal neurons where it is minimal. Here we show in acute rat hippocamal slices that insulin (1 nM) “turns on” new extrasynaptic GABA(A) channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The channels are activated by more than million times lower GABA concentrations than synaptic channels, generate tonic currents and show outward rectification. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC(50)) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA. They are inhibited by GABA(A) antagonists but have novel pharmacology as the benzodiazepine flumazenil and zolpidem are inverse agonists. The results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed and demonstrate an unexpected hormonal control of the inhibitory channel subtypes and excitability of hippocampal neurons. The insulin-induced new channels provide a specific target for rescuing cognition in health and disease. Public Library of Science 2011-01-14 /pmc/articles/PMC3021545/ /pubmed/21264261 http://dx.doi.org/10.1371/journal.pone.0016188 Text en Jin et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Jin, Zhe
Jin, Yang
Kumar-Mendu, Suresh
Degerman, Eva
Groop, Leif
Birnir, Bryndis
Insulin Reduces Neuronal Excitability by Turning on GABA(A) Channels that Generate Tonic Current
title Insulin Reduces Neuronal Excitability by Turning on GABA(A) Channels that Generate Tonic Current
title_full Insulin Reduces Neuronal Excitability by Turning on GABA(A) Channels that Generate Tonic Current
title_fullStr Insulin Reduces Neuronal Excitability by Turning on GABA(A) Channels that Generate Tonic Current
title_full_unstemmed Insulin Reduces Neuronal Excitability by Turning on GABA(A) Channels that Generate Tonic Current
title_short Insulin Reduces Neuronal Excitability by Turning on GABA(A) Channels that Generate Tonic Current
title_sort insulin reduces neuronal excitability by turning on gaba(a) channels that generate tonic current
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021545/
https://www.ncbi.nlm.nih.gov/pubmed/21264261
http://dx.doi.org/10.1371/journal.pone.0016188
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