Document Detail


Modulation of Cx46 hemichannels by nitric oxide.
MedLine Citation:
PMID:  19357237     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Gap-junction hemichannels are composed of six protein subunits (connexins). Undocked hemichannels contribute to physiological autocrine/paracrine cell signaling, including release of signaling molecules, cell-volume regulation, and glucose uptake. In addition, hemichannels may be pathologically activated by dephosphorylation and cell-membrane depolarization. Such hemichannel opening may induce and/or accelerate cell death. It has been suggested that connexin43 (Cx43) hemichannels are sensitive to redox potential changes and that one or more intracellular cysteines is/are important for this process. Cx46 is expressed in the lens, and its dysfunction induces cataract formation. It contains six cysteines in the extracellular loops, one in the fourth transmembrane helix, and two in the COOH-terminal domain. The latter may be susceptible to oxidation by nitric oxide (NO), which could be involved in cataract formation through cysteine S-nitrosylation. Here we report studies of the effects of the NO donor S-nitrosoglutathione (GSNO) on the electrical properties and fluorescent-dye permeability of wild-type Cx46 and mutant hemichannels expressed in Xenopus laevis oocytes. GSNO enhanced hemichannel voltage sensitivity, increased tail-current amplitude, and changed activation and closing kinetics in Cx46 and Cx46-CT43 (Cx46 mutant in which the COOH terminus was replaced with that of Cx43), but not in Cx46-C3A (Cx46 in which the intracellular and transmembrane helix 4 cysteines were mutated to alanine). We conclude that Cx46 hemichannels are sensitive to NO and that the NO effects are mediated by modification of one or more intracellular cysteines. However, it is unlikely that NO induces cataract formation due to the hemichannel activation, because at normal resting potential, NO had no major effects on Cx46 hemichannel permeability.
Authors:
Mauricio A Retamal; ShengYong Yin; Guillermo A Altenberg; Luis Reuss
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-04-08
Journal Detail:
Title:  American journal of physiology. Cell physiology     Volume:  296     ISSN:  0363-6143     ISO Abbreviation:  Am. J. Physiol., Cell Physiol.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-05-29     Completed Date:  2009-07-09     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  100901225     Medline TA:  Am J Physiol Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  C1356-63     Citation Subset:  IM    
Affiliation:
Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, and Center for Membrane Protein Research, Lubbock, Texas, USA. mretamal@udd.cl
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MeSH Terms
Descriptor/Qualifier:
Animals
Cataract / metabolism*
Connexin 43 / metabolism
Connexins / drug effects,  genetics,  metabolism*
Cysteine
Dithiothreitol / pharmacology
Fluorescent Dyes / metabolism
Gap Junctions / metabolism*
Ion Channel Gating* / drug effects
Kinetics
Membrane Potentials
Mutation
Nitric Oxide / metabolism*
Nitric Oxide Donors / pharmacology
Oocytes
Oxidation-Reduction
Permeability
Rats
Recombinant Fusion Proteins / metabolism
Reducing Agents / pharmacology
S-Nitrosoglutathione / pharmacology
Xenopus laevis
Grant Support
ID/Acronym/Agency:
GM-068586/GM/NIGMS NIH HHS; GM-79629/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Connexin 43; 0/Connexins; 0/Cx46 protein, rat; 0/Fluorescent Dyes; 0/Nitric Oxide Donors; 0/Recombinant Fusion Proteins; 0/Reducing Agents; 10102-43-9/Nitric Oxide; 3483-12-3/Dithiothreitol; 52-90-4/Cysteine; 57564-91-7/S-Nitrosoglutathione
Comments/Corrections

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