Signaling complexes of voltage-gated sodium and calcium channels

Membrane depolarization and intracellular Ca²⁺ transients generated by activation of voltage-gated Na⁺ and Ca²⁺ channels are local signals, which initiate physiological processes such as action potential conduction, synaptic transmission, and excitation–contraction coupling. Targeting of effector proteins and regulatory proteins to ion channels is an important mechanism to ensure speed, specificity, and precise regulation of signaling events in response to local stimuli. This article reviews experimental results showing that Na⁺ and Ca²⁺ channels form local signaling complexes, in which effector proteins, anchoring proteins, and regulatory proteins interact directly with ion channels. The intracellular domains of these channels serve as signaling platforms, mediating their participation in intracellular signaling processes. These protein–protein interactions are important for regulation of cellular plasticity through modulation of Na⁺ channel function in brain neurons, for short-term synaptic plasticity through modulation of presynaptic Ca_V2 channels, and for the fight-or-flight response through regulation of postsynaptic Ca_V1 channels in skeletal and cardiac muscle. These localized signaling complexes are essential for normal function and regulation of electrical excitability, synaptic transmission, and excitation–contraction coupling.