title: Calmodulin kinase II is required for fight or flight sinoatrial node physiology.
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.
authors.affiliation: Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa, 2256 CBRB, Iowa City, IA 52242, USA.
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Wu
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.forename: Biyi
authors.initials: B
authors.lastname: Chen
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.forename: Madhu V
authors.initials: MV
authors.lastname: Singh
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Guan
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.forename: Satyam
authors.initials: S
authors.lastname: Sarma
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Grumbach
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D002395:Catecholamines / Q000494:pharmacology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000502:physiology; D004924:Escape Reaction / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D051379:Mice; D018345:Mice, Knockout; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012849:Sinoatrial Node / Q000166:cytology / Q000502:physiology*
chemical_list: D002395:Catecholamines; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D011943:Receptors, Adrenergic, beta; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium