BPS2026 – Allosteric gating interactions between RyR channels justify intracellular Ca2+ release of skeletal muscle in quantitative detail

Back in 1988, Block et al. (JBC) revealed the curious “skipping” arrangement of voltage sensors (Ca V 1.1/DHPRs) and Ca 2+ release channels (RyRs) in the couplons of skeletal muscle, whereby DHPRs overlap alternate RyRs named “V,” leaving in-between “C” RyRs. The activation mechanism of these voltage-sensor-less channels has been a mystery ever since. I now show simulations that assume allosteric activation of C by V channels and reproduce in detail the time course of Ca 2+ release flux elicited by diverse pulse patterns in mammalian muscle. The model copies the coupon structure: every C channel contacts three V channels and vice-versa. Activation of V channels is determined by the membrane potential, which changes the free energies of the closed <-> open reaction. Gating of C channels is in turn controlled by state-dependent free energies that emerge from allosteric interactions with the contacting V channels, following rules set by Stern et al. (JGP 1999). Allostery opens the C channels; namely, when in contact with an open V channel, the free energy difference between the open and the closed C channel states decreases by eOO k B T . The decay of flux after its prominent peak is determined by transition of the C channels to an inactivated closed state. With 8 adjustable parameters, the model reproduces a vast set of observations (voltage dependence of peak and steady fluxes, kinetics of rise to and decay from the peak, deactivation) and approximates “quantal” conditioning (Pizarro et al., J. Physiol. 1997; Sárközi et al. JMRCM 2000). Together with recent structural evidence of intimate contact (Xu et al., Sci. Adv. 2024) and old evidence of coupling in bilayers (Marx et al., Science 1998) these simulations provide a compelling role for the sensor-less RyRs of skeletal muscle.