Sinoatrial nodal cell ryanodine receptor and Na(+)-Ca(2+) exchanger: molecular partners in pacemaker regulation.
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 Ca(2+) release during the DD produces a localized subsarcolemmal Ca(2+) increase that spreads in a wavelike manner by Ca(2+)-induced Ca(2+) release and produces an inward current via the Na(+)-Ca(2+) exchanger (NCX). Ryanodine, a blocker of the sarcoplasmic reticulum Ca(2+) release channel, in a dose-dependent manner reduces the SANC beating rate with an IC(50) of 2.6 micromol/L and abolishes the local Ca(2+) transients that precede the AP upstroke. In voltage-clamped cells in which the DD was simulated by voltage ramp, 3 micromol/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 Ca(2+) 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, Ca(2+) activation of the NCX, because of localized sarcoplasmic reticulum Ca(2+) release, is a critical element in a chain of molecular interactions that permits the heartbeat to occur and determines its beating rate.
Bogdanov
K Y
KY
Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Md, USA. BogdanovK@grc.nia.nih.gov
Vinogradova
T M
TM
Lakatta
E G
EG
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D008094:Lithium / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011817:Rabbits; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D012849:Sinoatrial Node / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism*
D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D012433:Ryanodine; D008094:Lithium; D002118:Calcium