Intracellular calcium release channels mediate their own countercurrent: the ryanodine receptor case study

Intracellular calcium release channels like ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP(3)Rs) mediate large Ca(2+) release events from Ca(2+) storage organelles lasting >5 ms. To have such long-lasting Ca(2+) efflux, a countercurrent of other ions is necessary to prevent the membrane potential from becoming the Ca(2+) Nernst potential in <1 ms. A recent model of ion permeation through a single, open RyR channel is used here to show that the vast majority of this countercurrent is conducted by the RyR itself. Consequently, changes in membrane potential are minimized locally and instantly, assuring maintenance of a Ca(2+)-driving force. This RyR autocountercurrent is possible because of the poor Ca(2+) selectivity and high conductance for both monovalent and divalent cations of these channels. The model shows that, under physiological conditions, the autocountercurrent clamps the membrane potential near 0 mV within approximately 150 mus. Consistent with experiments, the model shows how RyR unit Ca(2+) current is defined by luminal [Ca(2+)], permeable ion composition and concentration, and pore selectivity and conductance. This very likely is true of the highly homologous pore of the IP(3)R channel.