Abstract
The ryanodine receptor (RyR) releases Ca2+ out of the sacroplasmic reticulum (SR) and is therefore thought of a calcium channel. However, the most abundant divalent cation is Mg2+ (present at ∼1 mM both in the cytoplasm and the SR) and RyR has a very high affinity for symmetrically applied Mg2+. This is seen in single-channel recordings when even 1 mM of symmetric Mg2+ reduces the current from 10 mM luminal Ca2+ by ∼25%. Here it is shown why changes in [Mg2+] (e.g., due to ischemia or exercise) disproportionately affect unitary Ca2+ current, in addition to changing RyR open probability. A recent model of ion permeation through RyR is used to first describe the mechanism behind this high Mg2+ affinity and RyR's weak K+ affinity and then analyze their effect on Ca2+ release. Loosely speaking, [K+] defines the SR membrane potential and [Mg2+] defines unitary Ca2+ current for a fixed SR membrane potential and SR Ca2+ load. Counterintuitively, while K+ occupancy in the pore is low, K+ still provides the vast majority of countercurrent during Ca2+ release. Moreover, the opposite is true for Mg2+; unless [Mg2+] is unusually high, Mg2+ provides little countercurrent despite having the largest number of ions in the pore.
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