Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Seung-Kuy Cha; Chunfa Huang; Yaxian Ding; Xiaoping Qi; Chou-Long Huang; R. Tyler Miller

doi:10.1074/jbc.M110.160390

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Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Journal article

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Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Seung-Kuy Cha, Chunfa Huang, Yaxian Ding, Xiaoping Qi, Chou-Long Huang and R. Tyler Miller

The Journal of biological chemistry, Vol.286(3), pp.1828-1835

01/21/2011

DOI: 10.1074/jbc.M110.160390

PMCID: PMC3023478

PMID: 21084311

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Abstract

The Ca2+-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 Gαq reduced cell surface expression and current density of Kir4.1, and these effects were blocked by RGS4, a protein that blocks signaling via Gαi and Gαq. Other α subunits had insignificant effects. Knockdown of caveolin-1 blocked the effect of Gαq 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 Gαq and caveolin. These results provide a novel molecular basis for the inhibition of renal NaCl transport by the CaR.

Signal Transduction

G Protein-coupled Receptors (GPCR)

Heterotrimeric G Proteins

Kidney

Potassium Channels

Details

Title: Subtitle: Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1
Creators: Seung-Kuy Cha - The University of Texas Southwestern Medical Center
Chunfa Huang - Case Western Reserve University
Yaxian Ding - Case Western Reserve University
Xiaoping Qi - Case Western Reserve University
Chou-Long Huang - The University of Texas Southwestern Medical Center
R. Tyler Miller - the Departments of Medicine and
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.286(3), pp.1828-1835
DOI: 10.1074/jbc.M110.160390
PMID: 21084311
PMCID: PMC3023478
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: Elsevier Inc
Language: English
Date published: 01/21/2011
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984359827002771

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