Calcium regulation in cardiac myocytes is central to excitation-contraction coupling (ECC) and in mitochondrial and hypertrophic (Hyp) nuclear signaling. Ubiquitous Ca regulatory systems, Ca-calmodulin (CaM) dependent protein kinase II (CaMKll), calcineurin and inositol (1,4,5)P3 receptors (InsP3R) in myocytes have been implicated in altering ECC, arrhythmogenesis and nuclear signaling. This PPG has advanced understanding of these emergent fields during the current award. In this renewal, novel questions &methods will be used to deepen understanding of these areas with respect to ECC, mitochondrial signaling, Hyp &heart failure (HF). Four highly synergistic multidisciplinary projects are planned. Project I (Bers) focuses on critical aspects of cellular CaMKll in aims concerning: 1) acute CaM &CaMKll effects on ECC, 2) Ca/CaM-dependent nuclear signaling via HDAC and NFAT, 3) quantitative aspects of mitochondrial Ca signaling, and 4) altered CaMKll signaling in Hyp &HF (regarding ECC, arrhythmias &nuclear regulation). Project II (Blatter) focuses on cellular aspects of IP3 signaling in 3 aims (?Hyp &HF) concerning: 1) acute IP3R-mediated effects on ECC and arrhythmias, 2) the role of InsP3R in mitochondrial Ca signaling and oxidative stress, and 3) Ca coding and IP3R involvement in nuclear NFAT signaling. Project III (Molkentin) focuses on Ca signaling and hypertrophic signaling and will assess how 1) altered Na influx via Na channels and 2) altered Na efflux via Na/K-ATPase regulate myocyte Ca and Hyp, and 3) how cyclophilin D &permeability transition pore regulate mitochondrial Ca. Project IV (Brown) focuses on CaMKll isoform-specific targets and localization by assessing 1) CaMKIldeltaB(B vs. CaMKIldeltaC(c localization and targets, 2) functional consequences of CaMKll compartmentalization, 3) how CaMKll is involved in post-ischemic signaling and 4) how CaMKll alters mitochondrial function. Scientific cores will support these aims. Core B (Genefic Mouse Models) will develop unique mice (e.g. KO/transgenics for InsP3R, CaMKIIdelta/gamma(, PKD, Epac1/2) for whole animal &myocyte studies. Core C (HF Rabbits) will prepare and do some analysis of HF rabbits. This integrates experienced investigators with highly complementary expertise and perspective to tackle these questions in an interactive multidisciplinary approach. Results will greatly increase our understanding of the roles of CaMKll and InsP3R in cardiac myocytes during ECC, arrhythmogenesis &nuclear signaling in normal, Hyp and HF cardiac myocytes.

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Krull, Holly
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University of California Davis
Schools of Medicine
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Ljubojevic, Senka; Bers, Donald M (2015) Nuclear calcium in cardiac myocytes. J Cardiovasc Pharmacol 65:211-7
Bers, Donald M (2014) Cardiac sarcoplasmic reticulum calcium leak: basis and roles in cardiac dysfunction. Annu Rev Physiol 76:107-27
Xie, Yuanfang; Grandi, Eleonora; Bers, Donald M et al. (2014) How does ?-adrenergic signalling affect the transitions from ventricular tachycardia to ventricular fibrillation? Europace 16:452-7
Correll, Robert N; Eder, Petra; Burr, Adam R et al. (2014) Overexpression of the Na+/K+ ATPase ?2 but not ?1 isoform attenuates pathological cardiac hypertrophy and remodeling. Circ Res 114:249-56
Myles, Rachel C; Wang, Lianguo; Bers, Donald M et al. (2014) Decreased inward rectifying K+ current and increased ryanodine receptor sensitivity synergistically contribute to sustained focal arrhythmia in the intact rabbit heart. J Physiol :
Sankar, Natesan; deTombe, Pieter P; Mignery, Gregory A (2014) Calcineurin-NFATc regulates type 2 inositol 1,4,5-trisphosphate receptor (InsP3R2) expression during cardiac remodeling. J Biol Chem 289:6188-98
Walther, Stefanie; Pluteanu, Florentina; Renz, Susanne et al. (2014) Urocortin 2 stimulates nitric oxide production in ventricular myocytes via Akt- and PKA-mediated phosphorylation of eNOS at serine 1177. Am J Physiol Heart Circ Physiol 307:H689-700
Zhang, Dai-Min; Chai, Yongping; Erickson, Jeffrey R et al. (2014) Intracellular signalling mechanism responsible for modulation of sarcolemmal ATP-sensitive potassium channels by nitric oxide in ventricular cardiomyocytes. J Physiol 592:971-90
Kapoor, Nidhi; Maxwell, Joshua T; Mignery, Gregory A et al. (2014) Spatially defined InsP3-mediated signaling in embryonic stem cell-derived cardiomyocytes. PLoS One 9:e83715
Morotti, S; Edwards, A G; McCulloch, A D et al. (2014) A novel computational model of mouse myocyte electrophysiology to assess the synergy between Na+ loading and CaMKII. J Physiol 592:1181-97

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