CACNA2D1

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 (minus) 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 (this gene), 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 (ion conducting subunit), alpha-2/delta (this gene, auxiliary subunit), beta, and gamma—in a 1:1:1:1 stoichiometry.

Function

CACNA2D1 is a gene that encodes the alpha-2/delta-1 subunit of voltage-dependent 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 (but not 3 and 4) 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 (VWA) domain, which forms a divalent metal ion-dependent adhesion site (MIDAS) together with an extracellular aspartic acid residue on alpha-1 (D122 on alpha-1B).

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 (NMDAR), AMPA type glutamate receptors (AMPAR) 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.

References

References

1. (Jun 1994). "Localization of the gene encoding the alpha 2/delta subunit (CACNL2A) of the human skeletal muscle voltage-dependent Ca2+ channel to chromosome 7q21-q22 by somatic cell hybrid analysis". Genomics.
2. "Entrez Gene: CACNA2D1 calcium channel, voltage-dependent, alpha 2/delta subunit 1".
3. (June 2013). "Isolation and characterization of the 5´-upstream region of the human voltage-gated Ca(2+) channel α 2δ-1 auxiliary subunit gene: promoter analysis and regulation by transcription factor Sp1". Pflügers Archiv: European Journal of Physiology.
4. (16 July 2025). "Biochemistry and physiology of voltage-gated calcium channel trafficking: a target for gabapentinoid drugs.". Open Biology.
5. (March 2011). "Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states". PAIN.
6. (2012). "Jasper's Basic Mechanisms of the Epilepsies [Internet].". National Center for Biotechnology Information (US).
7. (18 July 2022). "Calcium channel auxiliary α2δ and β subunits: trafficking and one step beyond". Nature Reviews Neuroscience.
8. (July 2008). "New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels". Current Neurology and Neuroscience Reports.
9. (2016-04-01). "Mechanisms of the gabapentinoids andα2δ-1 calcium channel subunit in neuropathic pain". Pharmacology Research & Perspectives.
10. (2013-10-16). "α2δ-1 Gene Deletion Affects Somatosensory Neuron Function and Delays Mechanical Hypersensitivity in Response to Peripheral Nerve Damage". The Journal of Neuroscience.
11. (2009). "The Increased Trafficking of the Calcium Channel Subunit α2δ-1 to Presynaptic Terminals in Neuropathic Pain Is Inhibited by the α2δ Ligand Pregabalin". Journal of Neuroscience.
12. (2023). "Structural biology of voltage-gated calcium channels". Channels.
13. (2024). "Mechanism of Analgesia by Gabapentinoid Drugs: Involvement of Modulation of Synaptogenesis and Trafficking of Glutamate-Gated Ion Channels". The Journal of Pharmacology and Experimental Therapeutics.