Relative abundance of α2 Na+ pump isoform influences Na+–Ca2+ exchanger currents and Ca2+ transients in mouse ventricular myocytes

In the mouse, genetic reduction in the Na+, K+-ATPase α1 or α2 isoforms results in different functional phenotypes: heterozygous α2 isolated hearts are hypercontractile, whereas heterozygous α1 hearts are hypocontractile. We examined Na+/Ca2+ exchange (NCX) currents in voltage clamped myocytes (pipette [Na+] = 15 mM) induced by abrupt removal of extracellular Na+. In wild-type (WT) myocytes, peak exchanger currents were 0.59 ± 0.04 pA/pF (mean ± S.E.M., n =1 0). In α1+/– myocytes (α2 isoform increased by 54%), NCX current was reduced to 0.33 ± 0.05 (n = 9, P < 0.001) indicating a lower subsarcolemmal [Na+]. In α2+/– myocytes (α2 isoform reduced by 54%), the NCX current was increased to 0.89 ± 0.11 (n = 8, P = 0.03). The peak sarcolemmal Na+ pump currents activated by abrupt increase in [K+]o to 4 mM in voltage clamped myocytes in which the Na+ pump had been completely inhibited for 5 min by exposure to 0 [K+]o were similar in α1+/– (0.86 ± 0.12, n = 10) and α2+/– myocytes (0.94 ± 0.08 pA/pF, n = 16), and were slightly but insignificantly reduced relative to WT (1.03 ± 0.05, n = 24). The fluo-3 [Ca2+]i transient (F/Fo) in WT myocytes paced at 0.5 Hz was 2.18 ± 0.09, n = 34, was increased in α2+/– myocytes (F/Fo = 2.56 ± 0.14, n = 24, P = 0.02), and was decreased in α1+/– myocytes (F/Fo = 1.93 ± 0.08, n = 28, P < 0.05). Thus the α2 isoform rather than the α1 appears to influence Na+/Ca2+ exchanger currents [Ca2+]i transients, and contractility. This finding is consistent with the proposal that α2 isoform of the Na pump preferentially alters [Na+] in a subsarcolemmal micro-domain adjacent to Na+/Ca2+ exchanger molecules and SR Ca2+ release sites.