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

Research output: Contribution to journalArticle

36 Scopus citations

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 Abstract mechanism that involves Gαq and caveolin. These results provide a novel molecular basis for the inhibition of renal NaCl transport by the CaR.

Original languageEnglish (US)
Pages (from-to)1828-1835
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number3
DOIs
StatePublished - Jan 21 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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