Circulation Research. 2001
Published online before print June 7, 2001, doi: 10.1161/hh1201.092095
Published online before print June 7, 2001, doi: 10.1161/hh1201.092095
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© 2001 American Heart Association, Inc.
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Sinoatrial Nodal Cell Ryanodine Receptor and Na+-Ca2+ Exchanger
Molecular Partners in Pacemaker Regulation
From the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Md.
Correspondence to Konstantin Bogdanov, PhD, Laboratory of Cardiovascular Sciences, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail BogdanovK{at}grc.nia.nih.gov
Abstract
Abstract—The rate of spontaneous diastolic depolarization (DD) of sinoatrial nodal cells (SANCs) that triggers recurrent action potentials (APs) is a fundamental aspect of the heart’s pacemaker. Here, in experiments on isolated SANCs, using confocal microscopy combined with a patch clamp technique, we show that ryanodine receptor Ca2+ release during the DD produces a localized subsarcolemmal Ca2+ increase that spreads in a wavelike manner by Ca2+-induced Ca2+ release and produces an inward current via the Na+-Ca2+ exchanger (NCX). Ryanodine, a blocker of the sarcoplasmic reticulum Ca2+ release channel, in a dose-dependent manner reduces the SANC beating rate with an IC50 of 2.6 µmol/L and abolishes the local Ca2+ transients that precede the AP upstroke. In voltage-clamped cells in which the DD was simulated by voltage ramp, 3 µmol/L ryanodine decreased an inward current during the voltage ramp by 1.6±0.3 pA/pF (SEM, n=4) leaving the peak of L-type Ca2+ current unchanged. Likewise, acute blockade of the NCX (via rapid substitution of bath Na+ 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 to activation/inactivation of multiple ion channels, Ca2+ activation of the NCX, because of localized sarcoplasmic reticulum Ca2+ release, is a critical element in a chain of molecular interactions that permits the heartbeat to occur and determines its beating rate.
Key Words: sinoatrial node • automaticity • ryanodine receptor • Na+-Ca2+ exchange
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