Is ryanodine receptor a calcium or magnesium channel? Roles of K+ and Mg2+ during Ca2+ release

The ryanodine receptor (RyR) is a poorly selective channel that mediates Ca2+ release from intracellular Ca2+ stores. How RyR's selectivity between the physiological cations K+, Mg2+, and Ca2+ affects single-channel Ca2+ current amplitude is examined using a recent model of RyR permeation. It is found that K+ provides the vast majority of the countercurrent (through RyR itself) that is needed to prevent the sarcoplasmic reticulum (SR) membrane potential from changing and stopping Ca2+ release. Moreover, intra-pore competition between Ca2+ and Mg2+ defines single RyR Ca2+ current amplitude. Since both [Mg2+] and [Ca2+]SR can change during pathophysiological conditions, the RyR unitary Ca2+ current amplitude during Ca2+ release may change significantly due to this Ca2+/Mg2+ competition. Compared to the classic action of Mg2+ on RyR open probability, these Ca2+ current amplitude changes have as large or larger effects on overall RyR Ca2+ mobilization. A new aspect of RyR divalent versus monovalent selectivity is also identified where this kind of selectivity decreases as divalent concentration increases.