期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 14, 页码 5972-5977出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806422106
关键词
sarcoplasmic reticulum; cardiac pacemaker; calcium; isoproterenol; HCN4
资金
- National Institutes of Health (NIH) [R01 HL 079031, R01 HL 62494, R01 HL 70250, R01 HL084583, R01 HL083422, R01 HL 090905]
- AHA [0635056N]
- NIH/NHLBI [R01 HL 089598]
- University of Iowa Research Foundation
- Fondation Leducq Alliance for CaMKII Signaling in Heart Disease
The best understood fight or flight'' mechanism for increasing heart rate (HR) involves activation of a cyclic nucleotide-gated ion channel (HCN4) by beta-adrenergic receptor (beta AR) agonist stimulation. HCN4 conducts an inward pacemaker'' current (If) that increases the sinoatrial nodal (SAN) cell membrane diastolic depolarization rate (DDR), leading to faster SAN action potential generation. Surprisingly, HCN4 knockout mice were recently shown to retain physiological HR increases with isoproterenol (ISO), suggesting that other I(f)-independent pathways are critical to SAN fight or flight responses. The multifunctional Ca(2+) and calmodulin-dependent protein kinase II (CaMKII) is a downstream signal in the beta AR pathway that activates Ca(2+) homeostatic proteins in ventricular myocardium. Mice with genetic, myocardial and SAN cell CaMKII inhibition have significantly slower HRs than controls during stress, leading us to hypothesize that CaMKII actions on SAN Ca(2+) homeostasis are critical for beta AR agonist responses in SAN. Here we show that CaMKII mediates ISO HR increases by targeting SAN cell Ca(2+) homeostasis. CaMKII inhibition prevents ISO effects on SAN Ca(2+) uptake and release from intracellular sarcoplasmic reticulum (SR) stores that are necessary for increasing DDR. CaMKII inhibition has no effect on the ISO response in SAN cells when SR Ca(2+) release is disabled and CaMKII inhibition is only effective at slowing HRs during beta AR stimulation. These studies show the tightly coupled, but previously unanticipated, relationship of CaMKII to the beta AR pathway in fight or flight physiology and establish CaMKII as a critical signaling molecule for physiological HR responses to catecholamines.
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