Voltage-dependent calcium channel, N-type, alpha-1 subunit (VDCC_N_a1su)
Type: Family

Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins . The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.

Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.

The alpha-1 subunit forms the pore for the import of extracellular calcium ions and, though regulated by the other subunits, is primarily responsible for the pharmacological properties of the channel . It shares sequence characteristics with all voltage-dependent cation channels, and exploits the same 6-helix bundle structural motif -in both sodium and calcium channels, this motif is repeated 4 times within the sequence to give a 24-helix bundle. Within each of these repeats, 5 of the transmembrane (TM) segments (S1, S2, S3, S5, S6) are hydrophobic, while the other (S4) is positively charged and serves as the voltage-sensor. Several genes encoding alpha-1 subunits have been identified and can be divided into three functionally distinct families based on sequence homology -Cav1, Cav2 and Cav3 . The Cav1 family forms channels mediating L-type calcium currents, the Cav2 family mediates P/Q-, N-, and R-type calcium currents, while the Cav3 family mediates T-type calcium currents.

N-type calcium channels are composed from alpha-1B subunits. Experiments employing CTX have demonstrated the physiological importance of the N-type calcium channels in the nervous system, where they have a significant developmental role in the migration of immature neurons before the establishment of their synaptic circuit. In peripheral neurons, such as autonomic neurons, motor neurons and spinal cord neurons, they have also been shown to be critically involved in the release of neurotransmitters, including glutamate , gamma-amino-butyric acid, acetylcholine, dopamine and norepinephrine . N-type calcium channels are promising targets for the development of drugs to relieve chronic and neuropathic pain . Recently, it has been shown to be specifically blocked by ziconotide .