Research supported by NIH (USA) and PEDECIBA and CONICYT (Uruguay).
University of Heidelberg (2006) Proc Physiol Soc 4, SA2
Research Symposium: E. Rios1, B. S. Launikonis1, L. Royer1, J. Zhou1, G. Brum2
1. Section of Cellular Signalling, Rush University, Chicago, IL, USA. 2. Department de Biofisica, Medicina, Universidad de la Republica, Montevideo, Uruguay.
The functional cycle of striated muscles requires a fast contraction followed by full relaxation, which demand in turn a fast activation of Ca2+ release channels followed by their rapid closing. At the cell-wide level, this is manifested by a rapidly increasing Ca2+ release flux in response to cell membrane depolarization, followed by its spontaneous decay even if the depolarizing stimulus is maintained. At the local level of Ca2+ sparks, the changes in flux correspond to synchronized opening and closing of channel clusters. The termination of flux in Ca2+ sparks thus represents at the local level the physiologically relevant process of termination of Ca2+ release. While a growing body of evidence points at depletion of SR-lumenal Ca2+ as an agent of Ca2+ spark termination in the heart, the mechanism of termination remains unknown in skeletal muscle. We will report on advances in methods to study the Ca2+ store of skeletal muscle and the effects of its depletion, using the more developed studies in the cardiac field as a term of comparison. Global estimates of depletion upon release elicited by an action potential range between 5 and 20% in skeletal muscle, while in cardiac muscle they reach easily 40%. Estimates of local depletion after a spark are of less than 7% in skeletal muscle, but close to 50% in the heart. Frequency and morphology of sparks in skeletal muscle depend weakly on SR [Ca2+], while in cardiac ventricular muscle an increase in SR [Ca2+] is believed to strongly promote Ca2+ release and its decrease to terminate Ca2+ release. In sum, there is no evidence of a role of depletion in termination of Ca2+ release and sparks in skeletal muscle, in striking contrast with the wealth of support for this role in the heart. In spite of this missing control, sparks are briefer and more stereotyped in skeletal than cardiac muscle, suggesting the presence of an alternative mechanism. We will present preliminary data exploring two possibilities: (1) the inactivation of channels by released Ca2+ and (2) a gating role of the intra-SR protein calsequestrin, suggested - among other indications - by the surprising time course of intra-SR Ca2+ depletion during a Ca2+ spark.
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Where applicable, experiments conform with Society ethical requirements.