beta-Adrenergic signaling accelerates and synchronizes cardiac ryanodine receptor response to a single L-type Ca2+ channel. Export

@article{citeulike:5923287, abstract = {As the most prototypical G protein-coupled receptor, beta-adrenergic receptor (betaAR) regulates the pace and strength of heart beating by enhancing and synchronizing L-type channel (LCC) Ca(2+) influx, which in turn elicits greater sarcoplasmic reticulum (SR) Ca(2+) release flux via ryanodine receptors (RyRs). However, whether and how betaAR-protein kinase A (PKA) signaling directly modulates RyR function remains elusive and highly controversial. By using unique single-channel Ca(2+) imaging technology, we measured the response of a single RyR Ca(2+) release unit, in the form of a Ca(2+) spark, to its native trigger, the Ca(2+) sparklet from a single LCC. We found that acute application of the selective betaAR agonist isoproterenol (1 muM, </=20 min) increased triggered spark amplitude in an LCC unitary current-independent manner. The increased ratio of Ca(2+) release flux underlying a Ca(2+) spark to SR Ca(2+) content indicated that betaAR stimulation helps to recruit additional RyRs in synchrony. Quantification of sparklet-spark kinetics showed that betaAR stimulation synchronized the stochastic latency and increased the fidelity (i.e., chance of hit) of LCC-RyR intermolecular signaling. The RyR modulation was independent of the increased SR Ca(2+) content. The PKA antagonists Rp-8-CPT-cAMP (100 muM) and H89 (10 muM) both eliminated these effects, indicating that betaAR acutely modulates RyR activation via the PKA pathway. These results demonstrate unequivocally that RyR activation by a single LCC is accelerated and synchronized during betaAR stimulation. This molecular mechanism of sympathetic regulation will permit more fundamental studies of altered betaAR effects in cardiovascular diseases.}, author = {Zhou, Peng and Zhao, Yan-Ting T. and Guo, Yun-Bo B. and Xu, Shi-Ming M. and Bai, Shu-Hua H. and Lakatta, Edward G. and Cheng, Heping and Hao, Xue-Mei M. and Wang, Shi-Qiang Q.}, citeulike-article-id = {5923287}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0906560106}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19815510}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19815510}, day = {7}, doi = {10.1073/pnas.0906560106}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, month = {October}, posted-at = {2009-10-12 02:43:26}, priority = {2}, title = {{beta}-Adrenergic signaling accelerates and synchronizes cardiac ryanodine receptor response to a single L-type Ca2+ channel.}, url = {http://dx.doi.org/10.1073/pnas.0906560106}, year = {2009} }

TY - JOUR ID - citeulike:5923287 L3 - citeulike-article-id:5923287 N2 - As the most prototypical G protein-coupled receptor, beta-adrenergic receptor (betaAR) regulates the pace and strength of heart beating by enhancing and synchronizing L-type channel (LCC) Ca(2+) influx, which in turn elicits greater sarcoplasmic reticulum (SR) Ca(2+) release flux via ryanodine receptors (RyRs). However, whether and how betaAR-protein kinase A (PKA) signaling directly modulates RyR function remains elusive and highly controversial. By using unique single-channel Ca(2+) imaging technology, we measured the response of a single RyR Ca(2+) release unit, in the form of a Ca(2+) spark, to its native trigger, the Ca(2+) sparklet from a single LCC. We found that acute application of the selective betaAR agonist isoproterenol (1 muM, </=20 min) increased triggered spark amplitude in an LCC unitary current-independent manner. The increased ratio of Ca(2+) release flux underlying a Ca(2+) spark to SR Ca(2+) content indicated that betaAR stimulation helps to recruit additional RyRs in synchrony. Quantification of sparklet-spark kinetics showed that betaAR stimulation synchronized the stochastic latency and increased the fidelity (i.e., chance of hit) of LCC-RyR intermolecular signaling. The RyR modulation was independent of the increased SR Ca(2+) content. The PKA antagonists Rp-8-CPT-cAMP (100 muM) and H89 (10 muM) both eliminated these effects, indicating that betaAR acutely modulates RyR activation via the PKA pathway. These results demonstrate unequivocally that RyR activation by a single LCC is accelerated and synchronized during betaAR stimulation. This molecular mechanism of sympathetic regulation will permit more fundamental studies of altered betaAR effects in cardiovascular diseases. JF - Proceedings of the National Academy of Sciences of the United States of America SN - 1091-6490 TI - {beta}-Adrenergic signaling accelerates and synchronizes cardiac ryanodine receptor response to a single L-type Ca2+ channel. AU - Zhou, Peng AU - Zhao, Yan-Ting AU - Guo, Yun-Bo AU - Xu, Shi-Ming AU - Bai, Shu-Hua AU - Lakatta, Edward AU - Cheng, Heping AU - Hao, Xue-Mei AU - Wang, Shi-Qiang PY - 2009/10/07/ UR - http://dx.doi.org/10.1073/pnas.0906560106 ER -