Editorial Commentary A Leakage Leads to Failure Roles of Sarcoplasmic Reticulum Ca Leak via RyR2 in Heart Failure Progression

Cytosolic-free calcium (Ca 2 ) is a multifunctional intracellular messenger that regulates many different cellular processes in cardiac myocytes.1 A transient rise in intracellular free Ca concentrations ([Ca ]i) during excitationcontraction (E-C) coupling is required for initiating contraction of cardiac muscle. Membrane depolarization activates voltage-gated L-type Ca channels within the transverse tubules (invaginations of the sarcolemma), and extracellular Ca enters cardiac myocytes. The increased [Ca ]i in the junctional space between transverse tubules and the sarcoplasmic reticulum (SR) triggers the Ca -induced Ca release from the SR via ryanodine receptor (RyR2)/intracellular Ca release channels. The resultant transient rise in global [Ca ]i activates the myofilaments to produce cardiac contraction. Myocyte relaxation occurs when [Ca ]i levels decline quickly through transport by the Ca recycling proteins, such as SR Ca -ATPase (SERCA), which pumps Ca back into SR, and the Na /Ca exchanger, which extrudes Ca out of myocytes.1 In addition to its pivotal role in cardiac E-C coupling, [Ca ]i is also a critical regulator of multiple signaling transduction pathways, including activation of protein kinases or protein phosphatases and modulation of gene transcription and expression (Figure).2 SR Ca content reflects the balance between Ca uptake (via SERCA) and Ca efflux (via RyR2). A normal SR Ca content is the key for the maintenance of physiological [Ca ]i levels and, thus, normal contractile function of cardiac myocytes. Under conditions of persistent pathological stress on the heart, such as pressure overload–induced myocardial hypertrophy and heart failure (HF), SR Ca content is reduced, and [Ca ]i is increased. Both reduced Ca 2