AN ALLOSTERIC MODEL OF THE MOLECULAR-INTERACTIONS OF EXCITATION-CONTRACTION COUPLING IN SKELETAL-MUSCLE

A contact interaction is proposed to exist between the voltage sensor of the transverse tubular membrane of skeletal muscle and the calcium release channel of the sarcoplasmic reticulum. This interaction is giv en a quantitative formulation inspired in the Monod, Wyman, and Change ux model of allosteric transitions in hemoglobin (Monod, J., J. Wyman, and J.-P. Changeux. 1965. Journal of Molecular Biology. 12:88-118), a nd analogous to one proposed by Marks and Jones for voltage-dependent Ca channels (Marks, T. N., and S. W. Jones. 1992. Journal of General P hysiology. 99:367-390). The allosteric protein is the calcium release channel, a homotetramer, with two accessible states, closed and open. The kinetics and equilibrium of this transition are modulated by volta ge sensors (dihydropyridine receptors) pictured as four units per rele ase channel, each undergoing independent voltage-driven transitions be tween two states (resting and activating). For each voltage sensor tha t moves to the activating state, the tendency of the channel to open i ncreases by an equal (large) factor. The equilibrium and kinetic equat ions of the model are solved and shown to reproduce well a number of e xperimentally measured relationships including: charge movement (Q) vs . voltage, open probability of the release channel (P(o)) vs. voltage, the transfer function relationship P. vs. Q, and the kinetics of char ge movement, release activation, and deactivation. The main consequenc e of the assumption of allosteric coupling is that primary effects on the release channel are transmitted backward to the voltage sensor and give secondary effects. Thus, the model reproduces well the effects o f perchlorate, described in the two previous articles, under the assum ption that the primary effect is to increase the intrinsic tendency of the release channel to open, with no direct effects on the voltage se nsor. This modification of the open-closed equilibrium of the release channel causes a shift in the equilibrium dependency of charge movemen t with voltage. The paradoxical slowing of charge movement by perchlor ate also results from reciprocal effects of the channel on the alloste rically coupled voltage sensors. The observations of the previous arti cles plus the simulations in this article constitute functional eviden ce of allosteric transmission.