Abstract 500: High Basal Ca 2+ / Calmodulin Kinase II Activity Modulates Spontaneous Sarcoplasmic Reticulum Ca 2+ Cycling That Drives Normal Automaticity in Sinoatrial Nodal Cells
| Autor: | Yue Li, Syevda G. Sirenko, Tatiana M. Vinogradova, Alexey E. Lyashkov, Weizhong Zhu, Magdalena Juhaszova, Bruce Ziman, Su Wang, Edward G. Lakatta |
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| Rok vydání: | 2007 |
| Předmět: | |
| Zdroj: | Circulation. 116 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | The crucial dependence of normal automaticity of sinoatrial nodal cells (SANC) on CaMKII signaling has previously been linked to an effect to facilitate recovery from inactivation of L-type Ca 2+ channels. More recently, however, it has been discovered that spontaneous, rhythmic, local Ca 2+ releases (LCR’s) from sarcoplasmic reticulum (SR) activate Na + /Ca 2+ exchanger current, imparting an exponential increase to the later part of the spontaneous depolarization that brings the surface membrane to threshold to fire an action potential (AP). Here, in single isolated intact SANC, using the phosphorylation site-specific polyclonal antibody, we show (Fig. A ) that, basal state phospholamban (PLB) phosphorylation at Thr-17, a CaMKII phosphorylation site, is over 3 times greater in SANC than in ventricular cells (VC). The CaMKII inhibitor, KN-93, but not its inactive analog, KN-92, markedly inhibits (by 80%) PLB Thr-17 phosphorylation (Fig. B ). Confocal imaging of saponin permeablized SANC, superfused in physiological solution with 150nM free Ca 2+ and 0.5mM EGTA, showed that KN-93 reduced the LCR frequency by 80% (from 5.6 ± 1.5 to 1.1 ± 0.3/1s × 100 μm) and size by 50% (from 4.0 ± 0.3 to 2.0 ± 0.3 μm). Thus, in addition to an effect on L-type Ca 2+ channels, the high basal CaMKII activation (indexed by PLB phosphorylation at Thr-17) has a major effect to determine the characteristics of spontaneous LCR’s that initiate AP’s and control normal automaticity of SANC. |
| Databáze: | OpenAIRE |
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