Voltage-dependent calcium channel, L-type, alpha-1D subunit (LVDCC_a1dsu)
Type: Family

This entry represents the alpha-1D subunits of the Voltage-dependent calcium channel, L-type (LVDCC), which allow cells to slowly inactivate voltage-gated Ca2+ influx to weak depolarisations . This property allows them to participate in important physiological functions, such as tonic neurotransmitter release in cochlear inner hair cells . In addition, these properties make them ideally suited to contribute to subthreshold Ca2+ signalling, for example in hippocampal pyramidal cells . Mutations in this channel have been associated with autism spectrum disorders and epilepsy .

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.

L-type calcium channels are formed from alpha-1S, alpha-1C, alpha-1D, and alpha-1F subunits. They are widely distributed and are well characterised in the heart, smooth and skeletal muscle, and some neurons. Their primary functions are in both excitation-contraction and excitation-secretion coupling. In skeletal muscle, the L-type calcium channels act as a voltage sensor for excitation-contraction coupling, and in cardiac muscle, they provide a pathway for calcium influx. Mutations affecting L-type channel subunits result in three diseases: (1) muscular dystrophy, which is characterised by a lack of functional skeletal muscle; (2) hypokalaemic periodic paralysis, which is characterised by episodic attacks of skeletal muscle weakness; and (3) malignant hyperthermia, which is the main cause of death due to anaesthesia. 1,4-dihydropyridines act as antagonists of these 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.