期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：14
页码：5972-5977
DOI：10.1073/pnas.0806422106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 If-independent pathways are critical to SAN fight or flight responses. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is a downstream signal in the {beta}AR pathway that activates Ca2+ 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 Ca2+ homeostasis are critical for {beta}AR agonist responses in SAN. Here we show that CaMKII mediates ISO HR increases by targeting SAN cell Ca2+ homeostasis. CaMKII inhibition prevents ISO effects on SAN Ca2+ 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 Ca2+ 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.
