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Differential Effects of Voltage-Dependent Inactivation and Local Anesthetics on Kinetic Phases of Ca²⁺ Release in Frog Skeletal Muscle

Gustavo Brum ^*, Nazira Piriz ^*, Rafael DeArmas ^*, Eduardo Rios , Michael Stern  and Gonzalo Pizarro ^* 

^*Departamento de Biofísica, Facultad de Medicina and Sección Biofísica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay; Department of Physiology and Molecular Biophysics, Rush University, Chicago, Illinois USA; and National Institutes of Health, Bethesda, Maryland USA

Correspondence: Address reprint requests to Gonzalo Pizarro, Departamento de Biofísica, Facultad de Medicina, Gral. Flores 2125, Montevideo, Uruguay 11800. Fax: 5-982-924-8784; E-mail: gpizarro{at}fmed.edu.uy.

In voltage-clamped frog skeletal muscle fibers, Ca²⁺ release rises rapidly to a peak, then decays to a nearly steady state. The voltage dependence of the ratio of amplitudes of these two phases (p/s) shows a maximum at low voltages and declines with further depolarization. The peak phase has been attributed to a component of Ca²⁺ release induced by Ca²⁺, which is proportionally greater at low voltages. We compared the effects of two interventions that inhibit Ca²⁺ release: inactivation of voltage sensors, and local anesthetics reputed to block Ca²⁺ release induced by Ca²⁺. Holding the cells partially depolarized strongly reduced the peak and steady levels of Ca²⁺ release elicited by a test pulse and suppressed the maximum of the p/s ratio at low voltages. The p/s ratio increased monotonically with test voltage, eventually reaching a value similar to the maximum found in noninactivated fibers. This implies that the marked peak of Ca²⁺ release is a property of a cooperating collection of voltage sensors rather than individual ones. Local anesthetics reduced the peak of release flux at every test voltage, and the steady phase to a lesser degree. At variance with sustained depolarization, they made p/s low at all voltages. These observations were well-reproduced by the "couplon" model of dual control, which assumes that depolarization and anesthetics respectively, and selectively, disable its Ca²⁺-dependent or its voltage-operated channels. This duality of effects and their simulation under such hypotheses are consistent with the operation of a dual, two-stage control of Ca²⁺ release in muscle, whereby Ca²⁺ released through multiple directly voltage-activated channels builds up at junctions to secondarily open Ca²⁺-operated channels.

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