Magnesium Ions as Modulators of Voltage-Gated and Ligand-Gated Ion Channels in Central Neurons

Magnesium ions regulate synaptic and nonsynaptic neuronal excitability from intracellular (Mg²⁺<i>_i</i>) and extracellular (Mg²⁺<i>_o</i>) domains, modulating voltage- and ligand-gated ion channels. K+ inward rectifier (Kir) channel inward rectification arises from Mg²⁺<i>_i</i> blocking the pore and outward K⁺ current, while Mg²⁺<i>_o</i> targets external sites. Mg²⁺<i>_i</i> causes voltage-dependent Ca²⁺ voltage-gated (Ca_V) and Na⁺ voltage-gated (Na_V) channel block while phosphorylation modulates channel activity. Mg²⁺<i>_o</i> elicits direct voltage-dependent Ca_V channel block, and screens surface charge, and in Na_V channels reduces conduction and may cause depolarization by quantum tunneling across closed channels. Mg²⁺<i>_i</i> is an allosteric large conductance Ca²⁺-activated K⁺ (BK) channel activator, binding to low-affinity sites to alter Ca²⁺ and voltage sensitivity but reduces small conductance Ca²⁺-activated K⁺ (SK) channels' outward K⁺ current and induces inward rectification. N-Methyl-D-aspartate receptor (NMDAR) channels are inhibited by Mg²⁺<i>_i</i> binding within the pore, while Mg²⁺<i>_o</i> stabilizes excitability through voltage-dependent block, Mg²⁺<i>_o</i> forms Mg-ATP complex modifying purinergic P2X receptor (P2XR) channel affinity and gating and directly blocks the pore. Mg²⁺<i>_o</i> reduces gamma-aminobutyric acid type A receptor (GABA_AR) channel Cl^- current amplitude and augments susceptibility to blockers. Mg²⁺<i>_o</i> and Mg²⁺<i>_i</i> block nicotinic acetylcholine receptor (nAChR) channels through voltage-dependent pore binding and surface charge screening, impeding current flow and altering gating.