Regulation of current flow through ryanodine receptors by luminal Ca2+

Single-channel studies unequivocally demonstrate that changes in luminal [Ca2+] cause marked changes in conductance and gating although the precise mechanisms involved in the luminal Ca2+-induced changes in gating have not been fully resolved. Evidence from isolated vesicle studies and single cell work also point to a regulatory role for luminal Ca2+ in the control of SR Ca2+-release for muscle contraction. Outstanding issues which remain to be addressed include: (i) What are the changes in free [Ca2+] that occur at the luminal face of the RyR channels during EC-coupling. (ii) Does luminal Ca2+ affect gating by binding to luminal or cytosolic sites on RyR. (iii) What are the direct and indirect effects of calsequestrin on RyR gating.