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Diabetic Visceral Hypersensitivity Is Associated With Activation of Mitogen-Activated Kinase in Rat Dorsal Root Ganglia

OBJECTIVE: Diabetic patients often experience visceral hypersensitivity and anorectal dysfunction. We hypothesize that the enhanced excitability of colon projecting dorsal root ganglia (DRG) neurons observed in diabetes is caused by a decrease in the amplitude of the transient A-type K(+) (I(A)) cur...

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Autores principales: Grabauskas, Gintautas, Heldsinger, Andrea, Wu, Xiaoyin, Xu, Dabo, Zhou, ShiYi, Owyang, Chung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114390/
https://www.ncbi.nlm.nih.gov/pubmed/21515848
http://dx.doi.org/10.2337/db10-1507
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author Grabauskas, Gintautas
Heldsinger, Andrea
Wu, Xiaoyin
Xu, Dabo
Zhou, ShiYi
Owyang, Chung
author_facet Grabauskas, Gintautas
Heldsinger, Andrea
Wu, Xiaoyin
Xu, Dabo
Zhou, ShiYi
Owyang, Chung
author_sort Grabauskas, Gintautas
collection PubMed
description OBJECTIVE: Diabetic patients often experience visceral hypersensitivity and anorectal dysfunction. We hypothesize that the enhanced excitability of colon projecting dorsal root ganglia (DRG) neurons observed in diabetes is caused by a decrease in the amplitude of the transient A-type K(+) (I(A)) currents resulting from increased phosphorylation of mitogen-activated protein kinases (MAPK) and reduced opening of K(v)4.2 channels. RESEARCH DESIGN AND METHODS: We performed patch-clamp recordings of colon projecting DRG neurons from control and streptozotocin-induced diabetic (STZ-D) rats. Western blot analyses and immunocytochemistry studies were used to elucidate the intracellular signaling pathways that modulate the I(A) current. In vivo studies were performed to demonstrate that abnormal MAPK signaling is responsible for the enhanced visceromotor response to colorectal distention in STZ-D rats. RESULTS: Patch-clamp studies demonstrated that I(A) current was diminished in the colon projecting DRG neurons of STZ-D rats. Western blot analysis of STZ-D DRG neurons revealed increases in phosphorylated MAPK and K(V)4.2. In diabetic DRG neurons, increased intracellular Ca(2+) ([Ca(2+)](i)), protein kinase C (PKC), and MAPK were involved in the regulation of I(A) current through modulation of K(v)4.2. Hypersensitive visceromotor responses to colorectal distention in STZ-D rats were normalized by administration of MAPK inhibitor U0126. CONCLUSIONS: We demonstrated that reduction of the I(A) current in STZ-D DRG neurons is triggered by impaired [Ca(2+)](i) ion homeostasis, and this in turn activates the PKC-MAPK pathways, resulting in decreased opening of the K(v)4.2 channels. Hence, the PKC-MAPK–K(v)4.2 pathways represent a potential therapeutic target for treating visceral hypersensitivity in diabetes.
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spelling pubmed-31143902012-06-01 Diabetic Visceral Hypersensitivity Is Associated With Activation of Mitogen-Activated Kinase in Rat Dorsal Root Ganglia Grabauskas, Gintautas Heldsinger, Andrea Wu, Xiaoyin Xu, Dabo Zhou, ShiYi Owyang, Chung Diabetes Pathophysiology OBJECTIVE: Diabetic patients often experience visceral hypersensitivity and anorectal dysfunction. We hypothesize that the enhanced excitability of colon projecting dorsal root ganglia (DRG) neurons observed in diabetes is caused by a decrease in the amplitude of the transient A-type K(+) (I(A)) currents resulting from increased phosphorylation of mitogen-activated protein kinases (MAPK) and reduced opening of K(v)4.2 channels. RESEARCH DESIGN AND METHODS: We performed patch-clamp recordings of colon projecting DRG neurons from control and streptozotocin-induced diabetic (STZ-D) rats. Western blot analyses and immunocytochemistry studies were used to elucidate the intracellular signaling pathways that modulate the I(A) current. In vivo studies were performed to demonstrate that abnormal MAPK signaling is responsible for the enhanced visceromotor response to colorectal distention in STZ-D rats. RESULTS: Patch-clamp studies demonstrated that I(A) current was diminished in the colon projecting DRG neurons of STZ-D rats. Western blot analysis of STZ-D DRG neurons revealed increases in phosphorylated MAPK and K(V)4.2. In diabetic DRG neurons, increased intracellular Ca(2+) ([Ca(2+)](i)), protein kinase C (PKC), and MAPK were involved in the regulation of I(A) current through modulation of K(v)4.2. Hypersensitive visceromotor responses to colorectal distention in STZ-D rats were normalized by administration of MAPK inhibitor U0126. CONCLUSIONS: We demonstrated that reduction of the I(A) current in STZ-D DRG neurons is triggered by impaired [Ca(2+)](i) ion homeostasis, and this in turn activates the PKC-MAPK pathways, resulting in decreased opening of the K(v)4.2 channels. Hence, the PKC-MAPK–K(v)4.2 pathways represent a potential therapeutic target for treating visceral hypersensitivity in diabetes. American Diabetes Association 2011-06 2011-05-21 /pmc/articles/PMC3114390/ /pubmed/21515848 http://dx.doi.org/10.2337/db10-1507 Text en © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Pathophysiology
Grabauskas, Gintautas
Heldsinger, Andrea
Wu, Xiaoyin
Xu, Dabo
Zhou, ShiYi
Owyang, Chung
Diabetic Visceral Hypersensitivity Is Associated With Activation of Mitogen-Activated Kinase in Rat Dorsal Root Ganglia
title Diabetic Visceral Hypersensitivity Is Associated With Activation of Mitogen-Activated Kinase in Rat Dorsal Root Ganglia
title_full Diabetic Visceral Hypersensitivity Is Associated With Activation of Mitogen-Activated Kinase in Rat Dorsal Root Ganglia
title_fullStr Diabetic Visceral Hypersensitivity Is Associated With Activation of Mitogen-Activated Kinase in Rat Dorsal Root Ganglia
title_full_unstemmed Diabetic Visceral Hypersensitivity Is Associated With Activation of Mitogen-Activated Kinase in Rat Dorsal Root Ganglia
title_short Diabetic Visceral Hypersensitivity Is Associated With Activation of Mitogen-Activated Kinase in Rat Dorsal Root Ganglia
title_sort diabetic visceral hypersensitivity is associated with activation of mitogen-activated kinase in rat dorsal root ganglia
topic Pathophysiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114390/
https://www.ncbi.nlm.nih.gov/pubmed/21515848
http://dx.doi.org/10.2337/db10-1507
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