A full range of mouse sinoatrial node AP firing rates requires protein kinase A-dependent calcium signaling

作者：Liu Jie; Sirenko Syevda; Juhaszova Magdalena; Ziman Bruce; Shetty Veena; Rain Silvia; Shukla Shweta; Spurgeon Harold A; Vinogradova Tatiana M; Maltsev Victor A; Lakatta Edward G^*

来源：Journal of Molecular and Cellular Cardiology, 2011, 51(5): 730-739.

DOI：10.1016/j.yjmcc.2011.07.028

• Sinoatrial node
• Automaticity
• Adenylyl cyclase-cyclic amp-protein kinase a-Ca2+ Signaling Cascade
• Ca2+ cycling proteins
• Phospholamban phosphorylation
• Local Ca2+ releases

Recent perspectives on sinoatrial nodal cell (SANC)* function indicate that spontaneous sarcoplasmic reticulum (SR) Ca2+ cycling, i.e. an intracellular "Ca2+ clock," driven by cAMP-mediated, PICA-dependent phosphorylation, interacts with an ensemble of surface membrane electrogenic molecules ("surface membrane clock") to drive SANC normal automaticity. The role of AC-cAMP-PKA-Ca2+ signaling cascade in mouse, the species most often utilized for genetic manipulations, however, has not been systematically tested. Here we show that Ca2+ cycling proteins (e.g. RyR2, NCX1, and SERCA2) are abundantly expressed in mouse SAN and that spontaneous, rhythmic SR generated local Ca2+ releases (LCRs) occur in skinned mouse SANC, clamped at constant physiologic [Ca2+]. Mouse SANG also exhibits a high basal level of phospholamban (PLB) phosphorylation at the PICA-dependent site, Serine16. Inhibition of intrinsic PICA activity or inhibition of PDE in SANG, respectively: reduces or increases PLB phosphorylation, and markedly prolongs or reduces the LCR period: and markedly reduces or accelerates SAN spontaneous firing rate. Additionally, the increase in AP firing rate by PICA-dependent phosphorylation by beta-adrenergic receptor (beta-AR) stimulation requires normal intracellular Ca2+ cycling, because the beta-AR chronotropic effect is markedly blunted when SR Ca2+ cycling is disrupted. Thus, AC-cAMP-PKA-Ca2+ signaling cascade is a major mechanism of normal automaticity in mouse SANG. Published by Elsevier Ltd.

• 出版日期2011-11
• 单位NIH