© 2000 American Heart Association, Inc.
Cellular Biology |
Sinoatrial Node Pacemaker Activity Requires Ca2+/Calmodulin-Dependent Protein Kinase II Activation
From the Laboratory of Cardiovascular Sciences (T.M.V., Y.-Y.Z., K.Y.B., D.Y., M.K., H.C., R.-P.X.), National Institute of Aging, Gerontology Research Center, Baltimore, Md, and National Laboratory of Biomembrane and Membrane Biotechnology (D.Y., H.C.), College of Life Sciences, Beijing University, Beijing, China.
Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail xiaor{at}grc.nia.nih.gov \ © 2000 American Heart Association, Inc.
Abstract—Cardiac beating arises from the spontaneous rhythmic excitation of sinoatrial (SA) node cells. Here we report that SA node pacemaker activity is critically dependent on Ca2+/calmodulin-dependent protein kinase II (CaMKII). In freshly dissociated rabbit single SA node cells, inhibition of CaMKII by a specific peptide inhibitor, autocamtide-2 inhibitory peptide (AIP, 10 µmol/L), or by KN-93 (0.1 to 3.0 µmol/L), but not its inactive analog, KN-92, depressed the rate and amplitude of spontaneous action potentials (APs) in a dose-dependent manner. Strikingly, 10 µmol/L AIP and 3 µmol/L KN-93 completely arrested SA node cells, which indicates that basal CaMKII activation is obligatory to the genesis of pacemaker AP. To understand the ionic mechanisms of the CaMKII effects, we measured L-type Ca2+ current (ICa, L), which contributes both to AP upstroke and to pacemaker depolarization. KN-93 (1 µmol/L), but not its inactive analog, KN-92, decreased ICa, L amplitude from 12±2 to 6±1 pA/pF without altering the shape of the current-voltage relationship. Both AIP and KN-93 shifted the midpoint of the steady-state inactivation curve leftward and markedly slowed the recovery of ICa, L from inactivation. Similar results were observed using the fast Ca2+ chelator BAPTA, whereas the slow Ca2+ chelator EGTA had no significant effect, which suggests that CaMKII activity is preferentially regulated by local Ca2+ transients. Indeed, confocal immunocytochemical imaging showed that active CaMKII is highly localized beneath the surface membrane in the vicinity of L-type channels and that AIP and KN-93 significantly reduced CaMKII activity. Thus, we conclude that CaMKII plays a vital role in regulating cardiac pacemaker activity mainly via modulating ICa, L inactivation and reactivation, and local Ca2+ is critically involved in these processes.
Key Words: sinoatrial node • L-type Ca2+ channel • Ca2+/calmodulin-dependent kinase II • local Ca2+ signaling
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