Linked Life Data

21084311

Source:http://linkedlifedata.com/resource/pubmed/id/21084311

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2011-1-17
pubmed:abstractText
The Ca(2+)-sensing receptor (CaR) regulates salt and water transport in the kidney as demonstrated by the association of gain of function CaR mutations with a Bartter syndrome-like, salt-wasting phenotype, but the precise mechanism for this effect is not fully established. We found previously that the CaR interacts with and inactivates an inwardly rectifying K(+) channel, Kir4.1, which is expressed in the distal nephron that contributes to the basolateral K(+) conductance, and in which loss of function mutations are associated with a complex phenotype that includes renal salt wasting. We now find that CaR inactivates Kir4.1 by reducing its cell surface expression. Mutant CaRs reduced Kir4.1 cell surface expression and current density in HEK-293 cells in proportion to their signaling activity. Mutant, activated G?(q) reduced cell surface expression and current density of Kir4.1, and these effects were blocked by RGS4, a protein that blocks signaling via G?(i) and G?(q). Other ? subunits had insignificant effects. Knockdown of caveolin-1 blocked the effect of G?(q) on Kir4.1, whereas knockdown of the clathrin heavy chain had no effect. CaR had no comparable effect on the renal outer medullary K(+) channel, an apical membrane distal nephron K(+) channel that is internalized by clathrin-coated vesicles. Co-immunoprecipitation studies showed that the CaR and Kir4.1 physically associate with caveolin-1 in HEK cells and in kidney extracts. Thus, the CaR decreases cell surface expression of Kir4.1 channels via a mechanism that involves G?(q) and caveolin. These results provide a novel molecular basis for the inhibition of renal NaCl transport by the CaR.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
21
pubmed:volume
286
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1828-35
pubmed:meshHeading
pubmed-meshheading:21084311-Animals, pubmed-meshheading:21084311-Biological Transport, pubmed-meshheading:21084311-Caveolin 1, pubmed-meshheading:21084311-Clathrin Heavy Chains, pubmed-meshheading:21084311-Clathrin-Coated Vesicles, pubmed-meshheading:21084311-GTP-Binding Protein alpha Subunits, Gq-G11, pubmed-meshheading:21084311-Gene Expression Regulation, pubmed-meshheading:21084311-Gene Knockdown Techniques, pubmed-meshheading:21084311-HEK293 Cells, pubmed-meshheading:21084311-Humans, pubmed-meshheading:21084311-Nephrons, pubmed-meshheading:21084311-Potassium, pubmed-meshheading:21084311-Potassium Channels, Inwardly Rectifying, pubmed-meshheading:21084311-Rats, pubmed-meshheading:21084311-Receptors, Calcium-Sensing, pubmed-meshheading:21084311-Signal Transduction, pubmed-meshheading:21084311-Sodium Chloride, pubmed-meshheading:21084311-Water-Electrolyte Imbalance
pubmed:year
2011
pubmed:articleTitle
Calcium-sensing receptor decreases cell surface expression of the inwardly rectifying K+ channel Kir4.1.
pubmed:affiliation
Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural