Ca regulation in cardiac myocytes is central to excitation-contraction coupling (ECC) and is also involved in hypertrophic nuclear signaling, mitochondrial energy regulation and cell death. Two important and Ca regulatory systems, Ca-calmodulin (CaM) dependent protein kinase II (CaMKll) and inositol (1,4,5)P3 receptors (InsPsR) are present in myocytes, and have been increasingly implicated in regulating ECC, arrhythmogenesis and nuclear signaling (due in part to studies in this PPG). Indeed, CaMKll is emerging as a nodal point in ECC, arrhythmogenesis and signaling in hypertrophy (Hyp) and heart failure (HF). Overall goals here are to understand better how Ca and CaMKll function in cardiac myocytes with respect to acute Ca signaling (ECC &arrhythmogenesis), mitochondrial function and how both InsPaR and CaMKll may be involved in nuclear signaling (via class II histone deacetylases, HDACs) in hypertrophy &HF. Main experimental methods include confocal fluorescence imaging (of Ca indicators &other fluorescent probes) and voltage clamp in isolated adult cardiac myocytes and hearts (including from transgenic and knockout mice, and HF rabbits). This project has 4 aims.
Aim 1 will measure acute CaMKIIS effects on ECC, and also dynamics of CaM &CaMKll signaling in myocytes, including effects on Ca current facilitation, Na current, SR Ca release (diastolic &systolic) and frequency-dependent acceleration of relaxation.
Aim 2 will test novel hypotheses about Ca/CaM-dependent signaling bv CaMKll &calcineurin to the nucleus via HDAC &NFAT to better understand neurohumoral signaling in Hyo &HF.
Aim 3 will assess how mitochondrial [Cal is regulated in cardiac myocytes, quantitatively and locally, with an eye toward mitochondrial and cell death mechanisms.
Aim 4 will assess altered CaMKll signaling in Hyp &HF regarding ECC, arrhythmias &nuclear signaling. The proposed work will be highly interdigitated with all three other projects in the PPG, taking full advantage of complementary perspectives and expertise of the PPG team. The results will provide comprehensive new information regarding the roles of CaM, CaMKll, calcineurin, mitochondrial Ca and InsPa signaling in cardiac myocytes during ECC, arrhythmogenesis and nuclear signaling in normal ventricular myocytes and during hypertrophy and heart failure.

Public Health Relevance

; Cardiac myocyte calcium signaling is critical to the electrical activity which synchronizes the heartbeat, the contraction that pumps blood, energetic balance at the mitochondrial level, and the control of gene transcription. In heart failure or arrhythmias things go wrong in these pathways, contributing to heart malfunction. Here we will provide novel experimental results in careful quantitative studies, which will help to understand the fundamental workings of these systems critical to health and cardiac disease

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL080101-09
Application #
8697100
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
9
Fiscal Year
2014
Total Cost
$477,909
Indirect Cost
$65,580
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Hoeker, Gregory S; Hanafy, Mohamed A; Oster, Robert A et al. (2016) Reduced Arrhythmia Inducibility With Calcium/Calmodulin-dependent Protein Kinase II Inhibition in Heart Failure Rabbits. J Cardiovasc Pharmacol 67:260-5
Panama, Brian K; Korogyi, Adam S; Aschar-Sobbi, Roozbeh et al. (2016) Reductions in the Cardiac Transient Outward K+ Current Ito Caused by Chronic β-Adrenergic Receptor Stimulation Are Partly Rescued by Inhibition of Nuclear Factor κB. J Biol Chem 291:4156-65
Lu, Xiyuan; Kwong, Jennifer Q; Molkentin, Jeffery D et al. (2016) Individual Cardiac Mitochondria Undergo Rare Transient Permeability Transition Pore Openings. Circ Res 118:834-41
Uchinoumi, Hitoshi; Yang, Yi; Oda, Tetsuro et al. (2016) CaMKII-dependent phosphorylation of RyR2 promotes targetable pathological RyR2 conformational shift. J Mol Cell Cardiol 98:62-72
Kanaporis, Giedrius; Blatter, Lothar A (2016) Calcium-activated chloride current determines action potential morphology during calcium alternans in atrial myocytes. J Physiol 594:699-714
Miyamoto, Shigeki; Brown, Joan Heller (2016) Drp1 and Mitochondrial Autophagy Lend a Helping Hand in Adaptation to Pressure Overload. Circulation 133:1225-7
Bossuyt, Julie; Bers, Donald M (2015) Assessing GPCR and G protein signaling to the nucleus in live cells using fluorescent biosensors. Methods Mol Biol 1234:149-59
Grimm, Michael; Ling, Haiyun; Willeford, Andrew et al. (2015) CaMKIIδ mediates β-adrenergic effects on RyR2 phosphorylation and SR Ca(2+) leak and the pathophysiological response to chronic β-adrenergic stimulation. J Mol Cell Cardiol 85:282-91
Hohendanner, Felix; Maxwell, Joshua T; Blatter, Lothar A (2015) Cytosolic and nuclear calcium signaling in atrial myocytes: IP3-mediated calcium release and the role of mitochondria. Channels (Austin) 9:129-38
Erickson, Jeffrey R; Nichols, C Blake; Uchinoumi, Hitoshi et al. (2015) S-Nitrosylation Induces Both Autonomous Activation and Inhibition of Calcium/Calmodulin-dependent Protein Kinase II δ. J Biol Chem 290:25646-56

Showing the most recent 10 out of 194 publications