The role of phosphoinositide metabolism in Ca2+ signalling of skeletal muscle cells.

1. The mobilization of Ca2+ from intracellular stores by D-myo-inositol 1,4,5-triphosphate[Ins(1,4,5)P3] is now widely accepted as the primary link between plasma membrane receptors that stimulate phospholipase C and the subsequent increase in intracellular free Ca2+ that occurs when such receptors are activated (Berridge, 1993). Since the observations of Volpe et al. (1985) which showed that Ins(1,4,5)P3 could induce Ca2+ release from isolated terminal cisternae membranes and elicit contracture of chemically skinned muscle fibres, research has focused on the role of Ins(1,4,5)P3 in the generation of SR Ca2+ transients and in the mechanism of excitation-contraction coupling (EC-coupling). 2. The mechanism of signal transduction at the triadic junction during EC-coupling is unknown. Asymmetric charge movement and mechanical coupling between highly specialized triadic proteins has been proposed as the primary mechanism for voltage-activated generation of SR Ca2+ signals and subsequent contraction. Ins(1,4,5)P3 has also been proposed as the major signal transduction molecule for the generation of the primary Ca2+ transient produced during EC-coupling. 3. Investigations on the generation of Ca2+ transients by Ins(1,4,5)P3 have been conducted on ion channels incorporated into lipid bilayers, skinned and intact fibres and isolated membrane vesicles. Ins(1,4,5)P3 induces SR Ca2+ release and the enzymes responsible for its synthesis and degradation are present in muscle tissue. However, the sensitivity of the Ca2+ release mechanism to Ins(1,4,5)P3 is highly dependent on experimental conditions and on membrane potential. 4. While Ins(1,4,5)P3 may not be the major signal transduction molecule for the generation of the primary Ca2+ signal produced during voltage-activated contraction, this inositol polyphosphate may play a functional role as a modulator of EC-coupling and/or of the processes of myoplasmic Ca2+ regulation occurring on a time scale of seconds, during the events of contraction.