Mechanisms of Ca2+ release from sarcoplasmic reticulum of skeletal muscle

Abstract

Since the discovery of the ATP-dependent Ca2+ transport by SR a little over two decades ago, remarkable progress has been made in understanding the kinetic mechanism of Ca2+ transport and ATP hydrolysis and the role of phosphorylated enzyme intermediates in the energetics of active ion transport. Significant information has accumulated on the structure and composition of the SR membrane, on the primary amino acid sequence of the Ca2+-pump protein, and on the adaptive changes in the Ca2+-transport function during embryonic development and muscle activity. The discovery of the charge movement as a step in EC coupling and the use of novel optical probes for analyzing potential and calcium transients in living muscle changed the enigma of EC coupling into a well-defined problem that is clearly open to rational solutions. Studies on the structure, composition, and function of the isolated components of the T-SR system have just begun. The effectiveness of this approach will depend on successful maintenance of the functionally intact structure of the T-SR junction during the disruption of the muscle, which is required for the isolation of pure membrane elements. Reconstitution of a functionally competent junctional complex from isolated components is the ultimate aim of these studies, but the path toward that goal is so difficult that much of the mechanism of EC coupling may be solved by electrophysiologists, before reconstitution is achieved. The avalanche of information on Ca2+ releases induced by various agents under diverse and sometimes ill-defined conditions led to formulation of a series of hypothetical mechanisms. Of these, Ca2+-induced Ca2+ release promises to be an important element of the physiological Ca2+-release process, but few of the other proposed mechanisms can be eliminated from consideration at this stage. The impressive progress of the last few years has left several fundamental problems largely unsolved. Among these are the physical mode of translocation of Ca2+ across the membrane and the molecular mechanism of the coupling of Ca2+ transport to ATP hydrolysis; the regulation of the concentration of the Ca2+-pump protein and calcium in the SR of fast and slow skeletal, cardiac, and smooth muscles; the gating mechanisms that regulate the graded release of calcium from the SR and the composition and biochemical characterization of the triad; the role of SR membrane potential in the regulation of Ca2+ fluxes in vivo; the permeability of SR membranes in living muscle; the functional significance of protein-protein interactions in the SR with respect to Ca2+ transport and permeability control.(ABSTRACT TRUNCATED AT 400 WORDS)