Voltage-gated calcium channels

Abstract

Voltage-gated calcium (Ca(2+)) channels are key transducers of membrane potential changes into intracellular Ca(2+) transients that initiate many physiological events. There are ten members of the voltage-gated Ca(2+) channel family in mammals, and they serve distinct roles in cellular signal transduction. The Ca(V)1 subfamily initiates contraction, secretion, regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses in specialized sensory cells. The Ca(V)2 subfamily is primarily responsible for initiation of synaptic transmission at fast synapses. The Ca(V)3 subfamily is important for repetitive firing of action potentials in rhythmically firing cells such as cardiac myocytes and thalamic neurons. This article presents the molecular relationships and physiological functions of these Ca(2+) channel proteins and provides information on their molecular, genetic, physiological, and pharmacological properties.

Figure 1.

Signal transduction by voltage-gated Ca²⁺ channels. Ca²⁺ entering cells initiates numerous intracellular events, including contraction, secretion, synaptic transmission, enzyme regulation, protein phosphorylation/dephosphorylation, and gene transcription. (Inset) Subunit structure of voltage-gated Ca²⁺ channels. The five-subunit complex that forms high-voltage-activated Ca²⁺ channels is illustrated with a central pore-forming α1 subunit, a disulfide-linked glycoprotein dimer of α2 and δ subunits, an intracellular β subunit, and a transmembrane glycoprotein γ subunit (in some Ca²⁺ channel subtypes). As described in the text, this model is updated from the original description of the subunit structure of skeletal muscle Ca²⁺ channels. (Adapted from Takahashi et al. 1987).

Figure 2.

Subunit structure of Ca²⁺ channels. The structures of Ca²⁺ channel subunits are illustrated as transmembrane folding models; predicted α helices are depicted as cylinders; the lengths of lines correlate approximately to the lengths of the polypeptide segments represented; and the zigzag line on the δ subunit illustrates its glycophosphatidylinositol anchor.

Figure 3.

Three-dimensional architecture of Ca²⁺ channels. (A) Illustration of the skeletal muscle Ca_V1.1 channel based on cryo-electronmicroscopy. This drawing assumes pseudo-fourfold symmetry of the α1 subunit. The view shows the extracellular side with the α2 subunit. The α1, γ, and δ subunits are embedded into the lipid membrane (not shown), which separates the extracellular α2 subunit from the cytosol. α2 is anchored via the disulfide-linked δ subunit within the α1 subunit. The proposed model allows for a tight interaction between α1 and δ as well as α1 and γ. (B) Structure of the Ca_Vβ subunit with the α interaction domain (AID). Coordinates are for the Ca_Vβ2a–Ca_V1.2 AID complex with SH3 (green) and NK (blue) domains are indicated. V1, V2, and V3 show the locations of the three variable domains that are absent from the structure. The AID (red) binds to a deep groove in the NK domain. AID residues tyrosine, tryptophan, and isoleucine are shown as CPK. The remaining residues are shown as lines.

Figure 4.

Ca²⁺ channel signaling complexes. (A) The presynaptic Ca²⁺ channel signaling complex. A presynaptic Ca²⁺ channel α1 subunit is illustrated as a transmembrane folding diagram as in Figure 2. Sites of interaction of SNARE proteins (the synprint site), Gβγ subunits, protein kinase C (PKC), CaMKII, and CaM and CaS proteins are illustrated. IM, IQ-like motif; CBD, CaM binding domain. (B) The cardiac Ca²⁺ channel signaling complex. The carboxy-terminal domain of the cardiac Ca²⁺ channels is shown in expanded presentation to illustrate the regulatory interactions clearly. ABD, AKAP15 binding domain; DCRD, distal carboxy-terminal regulatory domain; PCRD, proximal carboxy-terminal regulatory domain; scissors, site of proteolytic processing. The DCRD binds to the PCRD through a modified leucine zipper interaction.