Sinoatrial Nodal Cell Ryanodine Receptor and Na + -Ca 2+ Exchanger: Molecular Partners in Pacemaker Regulation

• Published in: Circulation research 2001-06, Vol.88 (12), p.1254-1258
• Main Authors: Bogdanov, Konstantin Y, Vinogradova, Tatiana M, Lakatta, Edward G
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/hh1201.092095

Therate of spontaneous diastolic depolarization (DD) of sinoatrial nodal cells(SANCs) that triggers recurrent action potentials (APs) is a fundamentalaspect of the heart’s pacemaker. Here, in experiments on isolated SANCs,using confocal microscopy combined with a patch clamp technique, we show thatryanodine receptor Ca release during the DDproduces a localized subsarcolemmal Ca increase that spreads in a wavelike manner byCa -inducedCa release and produces an inward currentvia theNa -Ca exchanger (NCX). Ryanodine, a blocker of the sarcoplasmic reticulumCa release channel, in a dose-dependentmanner reduces the SANC beating rate with an IC 50 of2.6 μmol/L and abolishes the local Ca transients that precede the AP upstroke. In voltage-clamped cells in which theDD was simulated by voltage ramp, 3 μmol/L ryanodine decreased an inwardcurrent during the voltage ramp by 1.6±0.3 pA/pF (SEM, n=4)leaving the peak of L-type Ca currentunchanged. Likewise, acute blockade of the NCX (via rapid substitution of bathNa by Li )abolished SANC beating and reduced the inward current to a similar extent(1.7±0.4 pA/pF, n=4), as did ryanodine. Thus, in addition toactivation/inactivation of multiple ion channels,Ca activation of the NCX, because oflocalized sarcoplasmic reticulum Ca release,is a critical element in a chain of molecular interactions that permits theheartbeat to occur and determines its beatingrate.