A Leakage Leads to Failure

Abstract

Cytosolic-free calcium (Ca2+) is a multifunctional intracellular messenger that regulates many different cellular processes in cardiac myocytes.1 A transient rise in intracellular free Ca2+ concentrations ([Ca2+]i) during excitation-contraction (E-C) coupling is required for initiating contraction of cardiac muscle. Membrane depolarization activates voltage-gated L-type Ca2+ channels within the transverse tubules (invaginations of the sarcolemma), and extracellular Ca2+ enters cardiac myocytes. The increased [Ca2+]i in the junctional space between transverse tubules and the sarcoplasmic reticulum (SR) triggers the Ca2+-induced Ca2+ release from the SR via ryanodine receptor (RyR2)/intracellular Ca2+ release channels. The resultant transient rise in global [Ca2+]i activates the myofilaments to produce cardiac contraction. Myocyte relaxation occurs when [Ca2+]i levels decline quickly through transport by the Ca2+ recycling proteins, such as SR Ca2+-ATPase (SERCA), which pumps Ca2+ back into SR, and the Na+/Ca2+ exchanger, which extrudes Ca2+ out of myocytes.1 In addition to its pivotal role in cardiac E-C coupling, [Ca2+]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 Figure. Remodeling of the Ca2+-dependent signalosome during cardiac hypertrophy and HF. Under conditions of persistent pathological stress on the heart, SR Ca2+ content is reduced and [Ca2+]i is increased. Both reduced Ca2+ pumping by SERCA and increased SR Ca2+ leak via RyR2 may be responsible for the reduced SR Ca2+ content and increased [Ca2+]i.3 Other possible sources of the hypertrophy-associated increase in [Ca2+]i may be from increases in influx of extracellular Ca …