Differential effects of voltage-dependent inactivation and local anesthetics on kinetic phases of Ca2+ release in frog skeletal muscle.
In voltage-clamped frog skeletal muscle fibers, Ca(2+) 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 Ca(2+) release induced by Ca(2+), which is proportionally greater at low voltages. We compared the effects of two interventions that inhibit Ca(2+) release: inactivation of voltage sensors, and local anesthetics reputed to block Ca(2+) release induced by Ca(2+). Holding the cells partially depolarized strongly reduced the peak and steady levels of Ca(2+) 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 Ca(2+) 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 Ca(2+)-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 Ca(2+) release in muscle, whereby Ca(2+) released through multiple directly voltage-activated channels builds up at junctions to secondarily open Ca(2+)-operated channels.
Brum
Gustavo
G
Departamento de Biofísica, Facultad de Medicina, Montevideo, Uruguay.
Piriz
Nazira
N
DeArmas
Rafael
R
Rios
Eduardo
E
Stern
Michael
M
Pizarro
Gonzalo
G
D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D001001:Anura; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D011892:Rana catesbeiana; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity
D000779:Anesthetics, Local; D015220:Calcium Channels; D002118:Calcium