Cardiac expression of the Na+/Ca2+exchanger NCX1 is GATA factor dependent

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Abstract
The cardiac sarcolemmal Na+/Ca2+exchanger plays a primary role in Ca2+efflux and is important in regulating intracellular Ca2+and beat-to-beat contractility. Of the three Na+/Ca2+exchanger genes cloned (NCX1, NCX2, and NCX3), only NCX1 is expressed in cardiac myocytes. NCX1 has alternative promoters for heart, kidney, and brain tissue-specific transcripts. Analysis of the cardiac NCX1 promoter (at −336 bp) identified a cardiac-specific minimum promoter (at −137) and two GATA sites (at −75 and −145). In this study, gel shift and supershift analyses identified GATA-4 in primary neonatal cardiac myocytes. Site-directed mutagenesis of the GATA-4 site at −75 abolishes binding and reduces activity of the minimum and full-length promoters by >90 and ∼60%, respectively. Mutation of the GATA site at −145 reduces activity of the full-length promoter by ∼30%. Mutation of an E-box at −175 does not alter promoter activity.