CACNA2D1


Voltage-dependent calcium channel subunit alpha-2/delta-1 is a protein that in humans is encoded by the CACNA2D1 gene.

Gene

The CACNA2D1 gene is located on chromosome 7q21.11–q22, spanning genomic coordinates approximately 81,946,444 to 82,443,956 on the reverse strand according to the GRCh38 genome build. This gene is part of a family that includes several transcript variants generated by alternative splicing, highlighting its considerable genetic complexity. The promoter region of CACNA2D1 is characterized by a GC-rich sequence and multiple binding sites for the Sp1 transcription factor, rather than a typical TATA box.
In mammals, alpha-2/delta proteins are classified into four subtypes, each encoded by a separate but closely related gene: CACNA2D1, CACNA2D2, CACNA2D3, and CACNA2D4.
Alternate transcriptional splice variants of this gene have been observed, but have not been thoroughly characterized.

Structure

Voltage-dependent calcium channels are composed of a complex of four subunits—alpha-1, alpha-2/delta, beta, and gamma—in a 1:1:1:1 stoichiometry.

Function

CACNA2D1 is a gene that encodes the alpha-2/delta-1 subunit of calcium channel">calcium (biology)">calcium channels, which are essential for regulating the influx of calcium ions into cells during membrane polarization. This auxiliary subunit modulates calcium currents and affects the activation and inactivation kinetics of the channel, thereby playing a key role in cellular processes such as excitation–contraction coupling in muscle and signal transmission in neurons.

Clinical significance

In CACNA2D1 knockout mice, there is an observed decrease in calcium channel currents recorded from dorsal root ganglion neurons, chromaffin cells, and cardiomyocytes.

Neuropathic pain

Peripheral nerve injury leads to an increase in alpha-2/delta-1 expression in damaged dorsal root ganglion sensory neurons. Mice overexpressing alpha-2/delta-1 display neuropathic symptoms such as tactile allodynia and hyperalgesia, without nerve injury.

Cardiac dysfunction

Mutations in alpha-2/delta-1 are associated with several heart conditions including Brugada syndrome and short QT syndromes.

As a drug target

Alpha-2/delta proteins are believed to be the molecular target of the gabapentinoids gabapentin and pregabalin, which are used to treat epilepsy and neuropathic pain. Only alpha-2/delta subtypes 1 and 2 are substrates for gabapentinoid drug binding. Both pregabalin and gabapentin are known to reduce the trafficking of alpha-2/delta-1 to presynaptic terminals. Chronic pregabalin treatment in a rat neuropathic pain model, at a dose that allieviated allodynia, reversed the elevated alpha-2/delta-1 protein levels in the spinal cord and reduced calcium channel currents.

Interactions

Alpha-2/delta-1 associates with calcium channel alpha-1 subunits via its von Willebrand factor-A domain, which forms a divalent metal ion-dependent adhesion site together with an extracellular aspartic acid residue on alpha-1.
Recently, some studies have suggested that alpha-2/delta-1 proteins, in addition to calcium channels, interact directly with N-methyl-D-aspartate type glutamate receptors, AMPA type glutamate receptors and the extracellular adhesion protein, thrombospondin. However, several studies have been unable to replicate key aspects of the proposed alpha-2/delta-1–thrombospondin interaction.