Journal article
Calmodulin kinase II is required for fight or flight sinoatrial node physiology
Proceedings of the National Academy of Sciences - PNAS, Vol.106(14), pp.5972-5977
From the Cover
04/07/2009
DOI: 10.1073/pnas.0806422106
PMCID: PMC2667018
PMID: 19276108
Abstract
The best understood “fight or flight” mechanism for increasing heart rate (HR) involves activation of a cyclic nucleotide-gated ion channel (HCN4) by β-adrenergic receptor (βAR) 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 βAR 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 βAR 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 βAR stimulation. These studies show the tightly coupled, but previously unanticipated, relationship of CaMKII to the βAR pathway in fight or flight physiology and establish CaMKII as a critical signaling molecule for physiological HR responses to catecholamines.
Details
- Title: Subtitle
- Calmodulin kinase II is required for fight or flight sinoatrial node physiology
- Creators
- Yuejin Wu - Departments ofZhan Gao - Departments ofBiyi Chen - Departments ofOlha M Koval - Departments ofMadhu V Singh - Departments ofXiaoqun Guan - Departments ofThomas J Hund - Departments ofWilliam Kutschke - Departments ofSatyam Sarma - Departments of Molecular Physiology and Biophysics, and Medicine (in Cardiology), Baylor College of Medicine, One Baylor Plaza BCM335, Houston, TX 77030Isabella M Grumbach - Departments ofXander H. T Wehrens - Departments of Molecular Physiology and Biophysics, and Medicine (in Cardiology), Baylor College of Medicine, One Baylor Plaza BCM335, Houston, TX 77030Peter J Mohler - Departments ofLong-Sheng Song - Departments ofMark E Anderson - Departments of
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.106(14), pp.5972-5977
- Series
- From the Cover
- DOI
- 10.1073/pnas.0806422106
- PMID
- 19276108
- PMCID
- PMC2667018
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 04/07/2009
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984094552902771
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