Relative Abundance Of Alpha 2 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 alpha 1 or alpha 2 isoforms results in different functional phenotypes: heterozygous alpha 2 isolated hearts are hypercontractile, whereas heterozygous alpha 1 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 = 10). In alpha 1(+/-) myocytes (alpha 2 isoform, increased by 54%), NCX current was reduced to 0.33 +/- 0.05 (n = 9, P < 0.001) indicating a lower subsarcolemmal [Na+]. In alpha 2(+/-) myocytes (alpha 2 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 alpha 1(+/-) (0.86 +/- 0.12, n = 10) and alpha 2(+/-) 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/F-o) in WT myocytes paced at 0.5 Hz was 2.18 +/- 0.09, n = 34, was increased in alpha 2(+/-) myocytes (F/F-o = 2.56 +/- 0.14, n = 24, P = 0.02), and was decreased in alpha 1(+/-) myocytes (F/F-o = 1.93 +/- 0.08, n = 28, P < 0.05). Thus the alpha 2 isoform rather than the alpha 1 appears to influence Na+/Ca2+ exchanger currents [Ca2+](i) transients, and contractility. This finding is consistent with the proposal that alpha 2 isoform of the Na pump preferentially alters [Na+] in a subsarcolemmal micro-domain adjacent to Na+/Ca2+ exchanger molecules and SR Ca2+ release sites. (c) 2005 Elsevier Ltd. All rights reserved.