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Identification of an endogenous inhibitor of the cardiac Na+/Ca2+ exchanger, phospholemman.

Authors: Ahlers, BA  Zhang, XQ  Moorman, JR  Rothblum, LI  Carl, LL  Song, J  Wang, J  Geddis, LM  Tucker, AL  Mounsey, JP  Cheung, JY 
Citation: Ahlers BA, etal., J Biol Chem. 2005 May 20;280(20):19875-82. Epub 2005 Mar 17.
Pubmed: (View Article at PubMed) PMID:15774479
DOI: Full-text: DOI:10.1074/jbc.M414703200

Rapid and precise control of Na(+)/Ca(2+) exchanger (NCX1) activity is essential in the maintenance of beat-to-beat Ca(2+) homeostasis in cardiac myocytes. Here, we show that phospholemman (PLM), a 15-kDa integral sarcolemmal phosphoprotein, is a novel endogenous protein inhibitor of cardiac NCX1. Using a heterologous expression system that is devoid of both endogenous PLM and NCX1, we first demonstrated by confocal immunofluorescence studies that both exogenous PLM and NCX1 co-localized at the plasma membrane. Reciprocal co-immunoprecipitation studies revealed specific protein-protein interaction between PLM and NCX1. The functional consequences of direct association of PLM with NCX1 was the inhibition of NCX1 activity, as demonstrated by whole-cell patch clamp studies to measure NCX1 current density and radiotracer flux assays to assess Na(+)-dependent (45)Ca(2+) uptake. Inhibition of NCX1 by PLM was specific, because a single mutation of serine 68 to alanine in PLM resulted in a complete loss of inhibition of NCX1 current, although association of the PLM mutant with NCX1 was unaltered. In native adult cardiac myocytes, PLM co-immunoprecipitated with NCX1. We conclude that PLM, a member of the FXYD family of small ion transport regulators known to modulate Na(+)-K(+)-ATPase, also regulates Na(+)/Ca(2+) exchange in the heart.


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RGD Object Information
RGD ID: 1581354
Created: 2006-09-29
Species: All species
Last Modified: 2006-09-29
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.