Signaling complexes of voltage-gated sodium and calcium channels

Abstract

Membrane depolarization and intracellular Ca(2+) transients generated by activation of voltage-gated Na+ and Ca(2+) 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 Ca(2+) 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(V)2 channels, and for the fight-or-flight response through regulation of postsynaptic Ca(V)1 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.

Figure 1. A Na⁺ channel signaling complex with PKA

A. The brain Na_V1.2 channel is illustrated as a transmembrane folding diagram with α, β1, and β2 subunits and a PKA signaling complex. Transmembrane alpha helical segments are illustrated as cylinders. The gating charges of the S4 segments are denoted by +. The amino acid residues that form the selectivity filter are denoted by circles with -, +, or blank inside. Phosphorylation sites are indicated by P. The inactivation particle in the inactivation gate is indicated by h in a circle. Open circles indicate the regions that form the inactivation gate receptor. The extracellular domains of the β subunits are shown as immunoglobulin-like domains. The interaction of PKA and AKAP15 with an amphipathic alpha helix in beginning of the intracellular loop connecting domains I and II is shown. B. A similar diagram of the Na_V1.2 channel with the tyrosine phosphorylation signaling complex.

Figure 2. A presynaptic Ca²⁺ channel signaling complex

A. The subunits of calcium channels. B. Transmembrane folding diagrams of the calcium channel subunits. C. The presynaptic Ca²⁺ channel signaling complex. Sites of interaction of SNARE proteins (the synprint site), Gβγ subunits, protein kinase C (PKC), calmodulin and neuronal Ca²⁺ binding proteins (CBD), and Ca²⁺/calmodulin-dependent protein kinase II are illustrated.

Figure 3. The cardiac Ca²⁺ channel signaling complex

The Ca_V1.2 channel is illustrated as a transmembrane folding diagram. Proteolytic processing of the distal C-terminal domain is indicated. ABD, AKAP15 binding domain; DCRD, distal C-terminal regulatory domain; PCRD, proximal C-terminal regulatory domain; scissors, site of proteolytic processing.