Critical Review Calcium signaling dysfunction in heart disease Elizabeth J. Cartwright,* Tamer Mohamed, Delvac Oceandy, and Ludwig Neyses Cardiovascular Medicine Research Group, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK Abstract. In the heart, Ca 2þ is crucial for the regulation of contraction and intracellular signaling, processes, which are vital to the functioning of the healthy heart. Ca 2þ -activated signaling pathways must function against a background of large, rapid, and tightly regulated changes in intracellular free Ca 2þ concentrations during each contraction and relaxation cycle. This review highlights a number of proteins that regulate signaling Ca 2þ in both normal and pathological conditions including cardiac hypertrophy and heart failure, and discusses how these pathways are not regulated by the marked elevation in free intracellular calcium ([Ca 2þ ] i ) during contraction but require smaller sustained increases in Ca 2þ concentration. In addition, we present published evidence that the pool of Ca 2þ that regulates signaling is compartmentalized into distinct cellular microdomains and is thus distinct from that regulating contraction. V C 2011 International Union of Biochemistry and Molecular Biology, Inc. Volume 37, Number 3, May/June 2011, Pages 175–181  E-mail: elizabeth.j.cartwright@manchester.ac.uk Keywords: calcium signaling, cardiac hypertrophy, heart failure, genetically encoded calcium indicators 1. Introduction Worldwide more people die from cardiovascular diseases (CVD) than any other cause. Currently, close to 30% of all deaths are attributed to CVD, and despite the huge and ongoing research focus, the World Health Organization pre- dicts that by 2030, the number of people that will die annu- ally from this group of diseases will raise to approximately 24,000,000. Of the diseases and conditions grouped under the term CVD, heart failure (HF) is one of the commonest causes of morbidity and mortality. The incidence of heart failure increases rapidly with age and due to the progressive ageing of the population in developed countries, this makes HF, along with diabetes mellitus, the only two cardiovascular disease groups whose prevalence continues to rise [1]. De- spite improved interventions, HF has a dismal prognosis, with patients dying from progressive pump failure or ventric- ular arrhythmias, and the 5-year survival rate currently being as low as 53–62% [2]. Such mortality rates have been lik- ened to those associated with aggressive cancers such as those of the ovary, bowel, and prostate [3]. Heart failure is a complex syndrome virtually always initially associated with cardiac hypertrophy, which signifi- cantly raises the risk of cardiovascular-associated morbidity and mortality. In response to acute or chronic insults, the heart will undergo compensatory growth known as hypertro- phy. However, sustained stress subsequently leads to heart failure characterized by chamber dilation, reduced contractile function, interstitial fibrosis, myocyte apoptosis, and in many cases, potentially lethal cardiac arrhythmias. Changes in intracellular calcium dynamics are associated with both hypertrophy and heart failure, and in recent years, it has become clear that abnormalities in calcium transport and signaling are at the heart of cardiac contractile deficiency and the progression of hypertrophy and heart failure [4–8]. 1.1. Dual role of calcium in the heart: contractile Ca 21 and signaling Ca 21 It has long been known that Ca 2þ is central to the regulation of multiple functions in all types of cells. This is no different in cardiomyocytes, the muscle cells of the heart; here, Ca 2þ is essential for two major processes, contraction, and signal- ing. Each contraction and subsequent relaxation of the cardiac muscle requires a cyclical change in the cytosolic free Ca 2þ concentration ([Ca 2þ ] i ) from 10 nm to 1 lM. At a cellular level, this process, known as excitation-contraction (E-C) coupling, is regulated by a number of specialized ion Abbreviations: [Ca 2þ ] i , free intracellular calcium; CaMKII, Ca 2þ -calmodulin-dependent protein kinase II; CASK, calcium/calmodulin serine protein kinase; CVD, cardiovascular disease; DTG, double transgenic; E-C, excitation-contraction; GECI, genetically encoded calcium indicator; HDAC5, histone deacetylase 5; IP 3 , inositol 1,4,5-triphosphate; IP 3 R, inositol 1,4,5-triphosphate receptor; NFAT, nuclear factor of activated T-cells; nNOS, neuronal nitric oxide synthase; PMCA, plasma membrane calcium/calmodulin depend- ent ATPase; SR, sarcoplasmic reticulum; TAC, transverse aortic constriction; TRP, tran- sient receptor protein. *Address for correspondence: Elizabeth J. Cartwright, PhD, Cardiovascular Medicine Research Group, Manchester Academic Health Science Centre, University of Manchester, Room 1.302 Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom. Tel.: þ44 161 275 1629; Fax: þ44 161 275 5669; E-mail: elizabeth.j.cartwright@manchester.ac.uk. Received 9 November 2010; accepted 30 December 2010 DOI: 10.1002/biof.149 Published online 14 June 2011 in Wiley Online Library (wileyonlinelibrary.com) 175