Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 42, Pages 18028-18033Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0906560106
Keywords
beta-adrenergic receptor; calcium signaling; excitation-contraction coupling; isoproterenol; protein kinase A
Categories
Funding
- 973 Major State Basic Research Development Program of China [2004CB720007, 2007CB512100]
- 863 Program [2007AA02Z457]
- National Natural Science Foundation of China [30730013, 30721064, 30728012, 30630021]
- National Institutes of Health [R01 TW007269]
- National Institute on Aging of the National Institutes of Health
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As the most prototypical G protein-coupled receptor, beta-adrenergic receptor (beta AR) 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 beta AR-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 Ca2+ sparklet from a single LCC. We found that acute application of the selective beta AR agonist isoproterenol (1 mu M, <= 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 beta AR stimulation helps to recruit additional RyRs in synchrony. Quantification of sparklet-spark kinetics showed that beta AR 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 Ca2+ content. The PKA antagonists Rp-8-CPT-cAMP (100 mu M) and H89 (10 mu M) both eliminated these effects, indicating that beta AR acutely modulates RyR activation via the PKA pathway. These results demonstrate unequivocally that RyR activation by a single LCC is accelerated and synchronized during beta AR stimulation. This molecular mechanism of sympathetic regulation will permit more fundamental studies of altered beta AR effects in cardiovascular diseases.
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