Activation of reverse Na+-Ca2+exchange by the Na+current augments the cardiac Ca2+transient: evidence from NCX knockout mice
- 31 August 2010
- journal article
- research article
- Published by Wiley in The Journal of Physiology
- Vol. 588 (17), 3267-3276
- https://doi.org/10.1113/jphysiol.2010.187708
Abstract
The hypothesis that Na(+) influx during the action potential (AP) activates reverse Na(+)-Ca(2+) exchange (NCX) and subsequent entry of trigger Ca(2+) is controversial. We tested this hypothesis by monitoring intracellular Ca(2+) before and after selective inactivation of I(Na) prior to a simulated action potential in patch-clamped ventricular myocytes isolated from adult wild-type (WT) and NCX knockout (KO) mice. First, we inactivated I(Na) using a ramp prepulse to 45 mV. In WT cells, inactivation of I(Na) decreased the Ca(2+) transient amplitude by 51.1 +/- 4.6% (P < 0.001, n = 14) and reduced its maximum release flux by 53.0 +/- 4.6% (P < 0.001, n = 14). There was no effect on diastolic Ca(2+). In striking contrast, Ca(2+) transients in NCX KO cardiomyocytes were unaffected by the presence or absence of I(Na) (n = 8). We obtained similar results when measuring trigger Ca(2+) influx in myocytes with depleted sarcoplasmic reticulum. In WT cells, inactivation of I(Na) decreased trigger Ca(2+) influx by 37.8 +/- 6% and maximum rate of flux by 30.6 +/- 7.7% at 2.5 mm external Ca(2+) (P < 0.001 and P < 0.05, n = 9). This effect was again absent in the KO cells (n = 8). Second, exposure to 10 mum tetrodotoxin to block I(Na) also reduced the Ca(2+) transients in WT myocytes but not in NCX KO myocytes. We conclude that I(Na) and reverse NCX modulate Ca(2+) release in murine WT cardiomyocytes by augmenting the pool of Ca(2+) that triggers ryanodine receptors. This is an important mechanism for regulation of Ca(2+) release and contractility in murine heart.This publication has 29 references indexed in Scilit:
- Reporting ethical matters in The Journal of Physiology: standards and adviceThe Journal of Physiology, 2009
- Allosteric Activation of Na+-Ca2+ Exchange by L-Type Ca2+ Current Augments the Trigger Flux for SR Ca2+ Release in Ventricular MyocytesBiophysical Journal, 2008
- Regulation of Cardiac L-Type Ca2+ Current in Na+-Ca2+ Exchanger Knockout Mice: Functional Coupling of the Ca2+ Channel and the Na+-Ca2+ ExchangerBiophysical Journal, 2007
- Contribution of the Na+/Ca2+ Exchanger to Rapid Ca2+ Release in CardiomyocytesBiophysical Journal, 2006
- Functional Adult Myocardium in the Absence of Na + -Ca 2+ ExchangeCirculation Research, 2004
- Sodium-Calcium Exchange: A Molecular PerspectiveAnnual Review of Physiology, 2000
- Calcium Signaling in Transgenic Mice Overexpressing Cardiac Na+-Ca2+ ExchangerThe Journal of general physiology, 1997
- Gating of the Cardiac Ca 2+ Release Channel: the Role of Na + Current and Na + -Ca 2+ ExchangeScience, 1992
- Sodium Current-Induced Release of Calcium from Cardiac Sarcoplasmic ReticulumScience, 1990
- Sodium-Calcium Exchange in Excitable Cells: Fuzzy SpaceScience, 1990