ArticleProceedings of the National Academy of Sciences of the United States of America2009
Calmodulin kinase II is required for fight or flight sinoatrial node physiology.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 103 papers.
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Who cites it
103 citing papers in PubMed, 151 citations in OpenAlex.
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- Cardiac β2 adrenergic receptor deletion drives calmodulin kinase II upregulation to induce connective tissue growth factor in cardiac fibrosis and diastolic dysfunction.Function (Oxford, England) · 2025Article
- HCN4 channels sense temperature and determine heart rate responses to heat.Nature communications · 2025Article
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- Cutaneous Calcium/Calmodulin-Dependent Protein Kinase II-γ-Positive Sympathetic Nerves Secreting Norepinephrine Dictate Psoriasis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Pacemaker Channels and the Chronotropic Response in Health and Disease.Circulation research · 2024Review
- Studying CaMKII: Tools and standards.Cell reports · 2024Review
- Cationic peptides erase memories by removing synaptic AMPA receptors through endophilin-mediated endocytosis.Research square · 2023Article
- An improved reporter identifies ruxolitinib as a potent and cardioprotective CaMKII inhibitor.Science translational medicine · 2023Article
- Emergent activity, heterogeneity, and robustness in a calcium feedback model of the sinoatrial node.Biophysical journal · 2023Article
- CaMKII as a Therapeutic Target in Cardiovascular Disease.Annual review of pharmacology and toxicology · 2023Review
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- Emotional state as a modulator of autonomic and somatic nervous system activity in postural control: a review.Frontiers in neurology · 2023Review
- Heart failure in mice induces a dysfunction of the sinus node associated with reduced CaMKII signaling.The Journal of general physiology · 2022Article
- Paradigm shift: new concepts for HCN4 function in cardiac pacemaking.Pflugers Archiv : European journal of physiology · 2022Review
43 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
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 (betaAR) agonist stimulation. HCN4 conducts an inward "pacemaker" current (I(f)) 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 betaAR 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 betaAR 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 betaAR stimulation. These studies show the tightly coupled, but previously unanticipated, relationship of CaMKII to the betaAR pathway in fight or flight physiology and establish CaMKII as a critical signaling molecule for physiological HR responses to catecholamines.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.