Published online before print January 19, 2006, doi: 10.1161/01.RES.0000204575.94040.d1
© 2006 American Heart Association, Inc.
Cellular Biology |
High Basal Protein Kinase A–Dependent Phosphorylation Drives Rhythmic Internal Ca2+ Store Oscillations and Spontaneous Beating of Cardiac Pacemaker Cells
From the Laboratory of Cardiovascular Science (T.M.V., A.E.L., W.Z., A.M.R., S.S., D.Y., Y.-Y.Z., R.-P.X., H.C., M.D.S., V.A.M., E.G.L.), Gerontology Research Center, National Institute on Aging, NIH, Baltimore, Md; and the Department of Integrative Physiology and The Cardiovascular Research Institute (S.D., M.B., S.J., J.L.C.), University of North Texas Health Science Center, Fort Worth. Current address for Y.-Y.Z.: Schering-Plough Research Institute, Lafayette, NJ.
Correspondence to Edward G. Lakatta, MD, Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224-6825. E-mail LakattaE{at}grc.nia.nih.gov
Local, rhythmic, subsarcolemmal Ca2+ releases (LCRs) from the sarcoplasmic reticulum (SR) during diastolic depolarization in sinoatrial nodal cells (SANC) occur even in the basal state and activate an inward Na+-Ca2+ exchanger current that affects spontaneous beating. Why SANC can generate spontaneous LCRs under basal conditions, whereas ventricular cells cannot, has not previously been explained. Here we show that a high basal cAMP level of isolated rabbit SANC and its attendant increase in protein kinase A (PKA)-dependent phosphorylation are obligatory for the occurrence of spontaneous, basal LCRs and for spontaneous beating. Gradations in basal PKA activity, indexed by gradations in phospholamban phosphorylation effected by a specific PKA inhibitory peptide were highly correlated with concomitant gradations in LCR spatiotemporal synchronization and phase, as well as beating rate. Higher levels of basal PKA inhibition abolish LCRs and spontaneous beating ceases. Stimulation of ß-adrenergic receptors extends the range of PKA-dependent control of LCRs and beating rate beyond that in the basal state. The link between SR Ca2+ cycling and beating rate is also present in vivo, as the regulation of beating rate by local ß-adrenergic receptor stimulation of the sinoatrial node in intact dogs is markedly blunted when SR Ca2+ cycling is disrupted by ryanodine. Thus, PKA-dependent phosphorylation of proteins that regulate cell Ca2+ balance and spontaneous SR Ca2+ cycling, ie, phospholamban and L-type Ca2+ channels (and likely others not measured in this study), controls the phase and size of LCRs and the resultant Na+-Ca2+ exchanger current and is crucial for both basal and reserve cardiac pacemaker function.
Key Words: sinoatrial node • ß-adrenergic stimulation • protein kinase A • ryanodine receptors • local Ca2+ release
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Circ. Res. 2006 98: 437-439.
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