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

Peng Zhou, Yan Ting Zhao, Yun Bo Guo, Shi Ming Xu, Shu Hua Bai, Edward G. Lakatta, Heping Cheng, Xue Mei Hao, Shi Qiang Wang

Research output: Contribution to journalArticlepeer-review

Abstract

As the most prototypical G protein-coupled receptor, β-adrenergic receptor (βAR) regulates the pace and strength of heart beating by enhancing and synchronizing L-type channel (LCC) Ca2+ influx, which in turn elicits greater sarcoplasmic reticulum (SR) Ca2+ release flux via ryanodine receptors (RyRs). However, whether and how βAR-protein kinase A (PKA) signaling directly modulates RyR function remains elusive and highly controversial. By using unique single-channel Ca2+ imaging technology, we measured the response of a single RyR Ca2+ release unit, in the form of a Ca2+ spark, to its native trigger, the Ca 2+ sparklet from a single LCC. We found that acute application of the selective βAR agonist isoproterenol (1 μM, ≤20 min) increased triggered spark amplitude in an LCC unitary current-independent manner. The increased ratio of Ca2+ release flux underlying a Ca2+ spark to SR Ca2+ content indicated that βAR stimulation helps to recruit additional RyRs in synchrony. Quantification of sparklet-spark kinetics showed that βAR 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 μM) and H89 (10 μM) both eliminated these effects, indicating that βAR acutely modulates RyR activation via the PKA pathway. These results demonstrate unequivocally that RyR activation by a single LCC is accelerated and synchronized during βAR stimulation. This molecular mechanism of sympathetic regulation will permit more fundamental studies of altered βAR effects in cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)18028-18033
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number42
DOIs
StatePublished - Oct 20 2009

Keywords

  • Calcium signaling
  • Excitation-contraction coupling
  • Isoproterenol
  • Protein kinase A
  • β-adrenergic receptor

ASJC Scopus subject areas

  • General

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