PMID- 23002235
OWN - NLM
STAT- MEDLINE
DCOM- 20130131
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 46
DP  - 2012 Nov 9
TI  - Flow-sensitive K+-coupled ATP secretion modulates activity of the epithelial Na+ 
      channel in the distal nephron.
PG  - 38552-8
LID - 10.1074/jbc.M112.408476 [doi]
AB  - 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-beta4 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-beta4 null mice. ENaC in BK-beta4 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-beta4 null mice. Consequently, sodium excretion is 
      impaired in BK-beta4 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-beta4 null mice likely contributes to their elevated blood pressure.
FAU - Bugaj, Vladislav
AU  - Bugaj V
AD  - Department of Physiology, University of Texas Health Sciences Center, San 
      Antonio, Texas 78229, USA.
FAU - Sansom, Steven C
AU  - Sansom SC
FAU - Wen, Donghai
AU  - Wen D
FAU - Hatcher, Lori I
AU  - Hatcher LI
FAU - Stockand, James D
AU  - Stockand JD
FAU - Mironova, Elena
AU  - Mironova E
LA  - eng
GR  - R01 DK059594/DK/NIDDK NIH HHS/United States
GR  - R01 DK071014/DK/NIDDK NIH HHS/United States
GR  - R01 DK71014/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120921
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Connexins)
RN  - 0 (Epithelial Sodium Channels)
RN  - 0 (Kcnmb1 protein, mouse)
RN  - 0 (Large-Conductance Calcium-Activated Potassium Channel beta Subunits)
RN  - 0 (Sodium, Dietary)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - 9NEZ333N27 (Sodium)
SB  - IM
MH  - Adenosine Triphosphate/*chemistry/metabolism
MH  - Animals
MH  - Blood Pressure
MH  - Connexins/chemistry
MH  - Epithelial Sodium Channels/*metabolism
MH  - Homeostasis
MH  - Large-Conductance Calcium-Activated Potassium Channel beta 
      Subunits/*genetics/physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Nephrons/*metabolism
MH  - Patch-Clamp Techniques
MH  - Sodium/chemistry/metabolism
MH  - Sodium, Dietary/metabolism
PMC - PMC3493900
EDAT- 2012/09/25 06:00
MHDA- 2013/02/01 06:00
PMCR- 2013/11/09
CRDT- 2012/09/25 06:00
PHST- 2012/09/25 06:00 [entrez]
PHST- 2012/09/25 06:00 [pubmed]
PHST- 2013/02/01 06:00 [medline]
PHST- 2013/11/09 00:00 [pmc-release]
AID - S0021-9258(20)62321-3 [pii]
AID - M112.408476 [pii]
AID - 10.1074/jbc.M112.408476 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 Nov 9;287(46):38552-8. doi: 10.1074/jbc.M112.408476. Epub 2012 
      Sep 21.