Store-Operated Calcium Entry Channels: Potential Role in Cardiac Function

Introduction

Calcium’s role as a ubiquitous intracellular messenger is demonstrated by its central role in a wide range of cellular functions from cell growth, proliferation, function and even cell death. In order to elicit to cellular response, a cell recruits various pumps, exchangers and channels to regulate the concentration of Ca²⁺ (Berridge, Bootman, & Roderick, 2003; Prakriya & Lewis, 2015; J. W. Putney, 2011). The endoplasmic reticulum/sarcoplasmic reticulum (ER/SR) act as an intracellular storage of Ca²⁺, while plasma membrane (PM) channels regulate gating of Ca²⁺ from the extracellular space. Store operated Ca²⁺ entry (SOCE), is a major mechanism representing Ca²⁺ entry in many excitable and non-excitable cells. Since the first characterization of SOCE through electrophysiology, the two major components of the SOCE process were identified; the ER/SR Ca²⁺ sensor, stromal interaction molecule (STIM) and, the plasma membrane (PM) localized Orai protein as the store-operated channels (Fahrner, Derler, Jardin, & Romanin, 2013; J. W. Putney, 2011; Shaw & Feske, 2012). Upon depletion of inositol-1, 4, 5-trisphosphate (IP₃) or Ryanodine (RyR)-sensitive ER/SR stores, localized ER sensor STIM directly couples with PM Orai channels mediating Ca²⁺ influx. Since the depletion of ER/SR Ca²⁺ is the trigger for PM Ca²⁺ entry, this pathway was appropriately named “store operated Ca²⁺ entry”. SOCE-mediated Ca²⁺ entry not only allows for refilling of the ER/SR stores but also helps maintain Ca²⁺ homeostasis. The sustained entry of Ca²⁺ also serves other purposes such as activation of secretion, modulation of enzyme activation, and initiation of transcriptional signaling (J. W. Putney, 2011). Since SOCE-mediated Ca²⁺ influx is involved in vital cellular processes, it is not surprising that aberrant SOCE function has been implicated in many disease states including immunodeficiency, acute pancreatitis, Alzheimer’s disease, Duchenne muscular dystrophy and cardiac hypertrophy (Karlstad, Sun, & Singh, 2012; J. W. Putney, 2011)

Since its discovery, the SOCE phenomenon has been well characterized in non-excitable immune cells (Prakriya & Lewis, 2015; Shaw & Feske, 2012). Soon after, SOCE-induced Ca²⁺ influx was shown to play a critical role in excitable cell such as neurons, skeletal muscle cells, and cardiomyocytes (Hartmann et al., 2014; Liu, Xin, Benson, Allen, & Ju, 2015; Majewski & Kuznicki, 2015; Stiber et al., 2008; Tojyo, Morita, Nezu, & Tanimura, 2014). Several studies have demonstrated the expression of STIM and Orai in adult cardiomyoctes, ventricular myocardium, and the sinoatrial node (Wolkowicz et al., 2011; Zhu-Mauldin, Marsh, Zou, Marchase, & Chatham, 2012). In fact, strong evidence suggests that the STIM1 and Orai play a key role in the progression of cardiac hypertrophy. Recent investigations have shown the increased expression of STIM1 in a hypertrophic response (Collins, Zhu-Mauldin, Marchase, & Chatham, 2013). With advances in molecular techniques and transgenic models, studies have provided insight into the role of Orai and transient receptor potential (TRP) channels in the etiology of several cardiovascular diseases (Yue et al., 2015). The goal of this chapter is to provide an overview of our current understanding of molecular regulation of SOCE and highlight the role of STIM1/Orai-1-mediated SOCE in cardiomyocyte function and pathology.