Document Detail

Flow-sensitive K+-coupled ATP secretion modulates activity of the epithelial Na+ channel in the distal nephron.
MedLine Citation:
PMID:  23002235     Owner:  NLM     Status:  MEDLINE    
The epithelial Na(+) channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN) is under tonic inhibition by a local purinergic signaling system responding to changes in dietary sodium intake. Normal BK(Ca) channel function is required for flow-sensitive ATP secretion in the ASDN. We tested here whether ATP secreted through connexin channels in a coupled manner with K(+) efflux through BK(Ca) channels is required for inhibitory purinergic regulation of ENaC in response to increases in sodium intake. Inhibition of connexin channels relieves purinergic inhibition of ENaC. Deletion of the BK-β4 regulatory subunit, which is required for normal BK(Ca) channel function and flow-sensitive ATP secretion in the ASDN, suppresses increases in urinary ATP in response to increases in sodium intake. As a consequence, ENaC activity, particularly in the presence of high sodium intake, is inappropriately elevated in BK-β4 null mice. ENaC in BK-β4 null mice, however, responds normally to exogenous ATP, indicating that increases in activity do not result from end-organ resistance but rather from lowered urinary ATP. Consistent with this, disruption of purinergic regulation increases ENaC activity in wild type but not BK-β4 null mice. Consequently, sodium excretion is impaired in BK-β4 null mice. These results demonstrate that the ATP secreted in the ASDN in a BK(Ca) channel-dependent manner is physiologically available for purinergic inhibition of ENaC in response to changes in sodium homeostasis. Impaired sodium excretion resulting form loss of normal purinergic regulation of ENaC in BK-β4 null mice likely contributes to their elevated blood pressure.
Vladislav Bugaj; Steven C Sansom; Donghai Wen; Lori I Hatcher; James D Stockand; Elena Mironova
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-09-21
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-12     Completed Date:  2013-01-31     Revised Date:  2013-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38552-8     Citation Subset:  IM    
Department of Physiology, University of Texas Health Sciences Center, San Antonio, Texas 78229, USA.
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MeSH Terms
Adenosine Triphosphate / chemistry*,  metabolism
Blood Pressure
Connexins / chemistry
Epithelial Sodium Channels / metabolism*
Large-Conductance Calcium-Activated Potassium Channel beta Subunits / genetics*,  physiology
Mice, Inbred C57BL
Mice, Transgenic
Nephrons / metabolism*
Patch-Clamp Techniques
Sodium / chemistry,  metabolism
Sodium, Dietary / metabolism
Grant Support
Reg. No./Substance:
0/Connexins; 0/Epithelial Sodium Channels; 0/Kcnmb1 protein, mouse; 0/Large-Conductance Calcium-Activated Potassium Channel beta Subunits; 0/Sodium, Dietary; 56-65-5/Adenosine Triphosphate; 7440-23-5/Sodium

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