CACNA2D1

CACNA2D1
Identifiers
Aliases	CACNA2D1 , CACNA2, CACNL2A, CCHL2A, LINC01112, lncRNA-N3, calcium voltage-gated channel auxiliary subunit alpha2delta 1
External IDs	OMIM: 114204; MGI: 88295; HomoloGene: 579; GeneCards: CACNA2D1; OMA:CACNA2D1 - orthologs
Gene location (Human) Chr. Chromosome 7 (human) [1] Band 7q21.11 Start 81,946,444 bp [1] End 82,443,777 bp [1]
Gene location (Mouse) Chr. Chromosome 5 (mouse) [2] Band 5 A2- A3|5 6.56 cM Start 16,139,689 bp [2] End 16,579,509 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in biceps brachii Skeletal muscle tissue of biceps brachii Skeletal muscle tissue of rectus abdominis body of tongue endothelial cell postcentral gyrus Brodmann area 23 entorhinal cortex right ventricle middle temporal gyrus Top expressed in triceps brachii muscle temporal muscle digastric muscle ankle sternocleidomastoid muscle ventromedial nucleus muscle of thigh vastus lateralis muscle dorsomedial hypothalamic nucleus body of femur More reference expression data BioGPS More reference expression data
Gene ontology Molecular function voltage-gated calcium channel activity metal ion binding voltage-gated ion channel activity calcium channel activity voltage-gated calcium channel activity involved in cardiac muscle cell action potential voltage-gated calcium channel activity involved in bundle of His cell action potential Cellular component voltage-gated calcium channel complex L-type voltage-gated calcium channel complex integral component of membrane T-tubule plasma membrane extracellular exosome membrane sarcoplasmic reticulum Biological process regulation of ion transmembrane transport regulation of calcium ion transport cardiac conduction ion transport calcium ion transmembrane transport calcium ion transport transport cardiac muscle cell action potential involved in contraction calcium ion transport into cytosol positive regulation of high voltage-gated calcium channel activity regulation of heart rate by cardiac conduction calcium ion transmembrane transport via high voltage-gated calcium channel regulation of ventricular cardiac muscle cell membrane repolarization regulation of membrane repolarization during action potential membrane depolarization during bundle of His cell action potential calcium ion import across plasma membrane regulation of calcium ion transmembrane transport via high voltage-gated calcium channel cellular response to amyloid-beta Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 781 12293 Ensembl ENSG00000153956 ENSMUSG00000040118 UniProt P54289 O08532 RefSeq (mRNA) NM_000722 NM_001302890 NM_001366867 NM_001110843 NM_001110844 NM_001110845 NM_001110846 NM_009784 RefSeq (protein) NP_000713 NP_001289819 NP_001353796 NP_001104313 NP_001104314 NP_001104315 NP_001104316 NP_033914 Location (UCSC) Chr 7: 81.95 – 82.44 Mb Chr 5: 16.14 – 16.58 Mb PubMed search [3] [4]
Wikidata
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Voltage-dependent calcium channel subunit alpha-2/delta-1 is a protein that in humans is encoded by the CACNA2D1 gene. ^{[5] [6]}

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. ^[7]

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. ^[6]

Alternate transcriptional splice variants of this gene have been observed, but have not been thoroughly characterized. ^[6]

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. ^[6]

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. ^[6]

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. ^[8]

Neuropathic pain

Peripheral nerve injury leads to an increase in alpha-2/delta-1 expression in damaged dorsal root ganglion sensory neurons. ^[9] Mice overexpressing alpha-2/delta-1 display neuropathic symptoms such as tactile allodynia and hyperalgesia, without nerve injury. ^[10]

Cardiac dysfunction

Mutations in alpha-2/delta-1 are associated with several heart conditions including Brugada syndrome and short QT syndromes. ^[11]

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. ^{[12] [13] [14]} 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. ^[10] 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. ^[15]

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). ^[16]

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. ^[17] However, several studies have been unable to replicate key aspects of the proposed alpha-2/delta-1–thrombospondin interaction. ^[8]

See also

• Voltage-dependent calcium channel
• Gabapentinoid drugs

References

1. GRCh38: Ensembl release 89: ENSG00000153956 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000040118 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Powers PA, Scherer SW, Tsui LC, Gregg RG, Hogan K (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. 19 (1): 192–193. doi:10.1006/geno.1994.1044. PMID   8188232.
6. "Entrez Gene: CACNA2D1 calcium channel, voltage-dependent, alpha 2/delta subunit 1".
7. Martínez-Hernández E, González-Ramírez R, Sandoval A, Cisneros B, Delgado-Lezama R, Felix R (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". Pflugers Archiv : European Journal of Physiology. 465 (6): 819–28. doi:10.1007/s00424-012-1194-8. PMID   23242029.
8. Dolphin A (16 July 2025). "Biochemistry and physiology of voltage-gated calcium channel trafficking: a target for gabapentinoid drugs". Open Biology. 15 (7) 250013. doi:10.1098/rsob.250013. PMID   40664238 – via The Royal Society Publishing.
9. Boroujerdi A, Zeng J, Sharp K, Kim D, Steward O, Luo ZD (March 2011). "Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states". PAIN. 152 (3): 649–655. doi:10.1016/j.pain.2010.12.014. PMC   3039050 . PMID   21239111 – via Elsevier Science Direct.
10. Dolphin A (2012). "Calcium channel α2δ subunits in epilepsy and as targets for antiepileptic drugs". In Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds.). Jasper's Basic Mechanisms of the Epilepsies [Internet] (4th ed.). Bethesda, Maryland, USA: National Center for Biotechnology Information (US).
11. Dolphin A (18 July 2022). "Calcium channel auxiliary α2δ and β subunits: trafficking and one step beyond". Nature Reviews Neuroscience. 13 (8): 542–555. doi:10.1038/nrn3311. PMID   22805911.
12. Rogawski MA, Bazil CW (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. 8 (4): 345–352. doi:10.1007/s11910-008-0053-7. PMC   2587091 . PMID   18590620.
13. Patel R, Dickenson AH (2016-04-01). "Mechanisms of the gabapentinoids andα2δ-1 calcium channel subunit in neuropathic pain". Pharmacology Research & Perspectives. 4 (2): e00205. doi:10.1002/prp2.205. ISSN   2052-1707. PMC   4804325 . PMID   27069626.
14. Patel R, Bauer CS, Nieto-Rostro M, Margas W, Ferron L, Chaggar K, et al. (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. 33 (42): 16412–16426. doi:10.1523/jneurosci.1026-13.2013. PMC   3797367 . PMID   24133248.
15. Bauer CS, Nieto-Rostro M, Rahman W, Tran-Van-Minh A, Ferron L, Douglas L, et al. (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. 29 (13): 4076–4088. doi:10.1523/jneurosci.0356-09.2009. PMC   6665374 . PMID   19339603.
16. Yao X, Gao S, Yan N (2023). "Structural biology of voltage-gated calcium channels". Channels. 18 (1): 2290807. doi:10.1080/19336950.2023.2290807. PMC   10761187 . PMID   38062897 – via Taylor & Francis Online.
17. Varadi G (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. 388 (1): 121–133. doi: 10.1124/jpet.123.001669 . ISSN   0022-3565. PMID   37918854.

Further reading

• Williams ME, Feldman DH, McCue AF (Jan 1992). "Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype". Neuron. 8 (1): 71–84. doi:10.1016/0896-6273(92)90109-Q. PMID   1309651. S2CID   39341712.
• Ellis SB, Williams ME, Ways NR (Sep 1988). "Sequence and expression of mRNAs encoding the alpha 1 and alpha 2 subunits of a DHP-sensitive calcium channel". Science. 241 (4873). New York, N.Y.: 1661–1664. Bibcode:1988Sci...241.1661E. doi:10.1126/science.2458626. PMID   2458626.
• Iles DE, Lehmann-Horn F, Scherer SW (Jun 1994). "Localization of the gene encoding the alpha 2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families". Human Molecular Genetics. 3 (6): 969–975. doi:10.1093/hmg/3.6.969. PMID   7951247.
• Brust PF, Simerson S, McCue AF (Nov 1993). "Human neuronal voltage-dependent calcium channels: studies on subunit structure and role in channel assembly". Neuropharmacology. 32 (11): 1089–1102. doi:10.1016/0028-3908(93)90004-M. PMID   8107964. S2CID   33257989.
• The Sanger Centre, The Washington University Genome Sequencing Cente (Nov 1998). "Toward a complete human genome sequence". Genome Research. 8 (11): 1097–1108. doi: 10.1101/gr.8.11.1097 . PMID   9847074.
• Schleithoff L, Mehrke G, Reutlinger B, Lehmann-Horn F (Oct 1999). "Genomic structure and functional expression of a human alpha(2)/delta calcium channel subunit gene (CACNA2)". Genomics. 61 (2): 201–209. doi:10.1006/geno.1999.5941. PMID   10534405.
• Bell DC, Butcher AJ, Berrow NS (Feb 2001). "Biophysical properties, pharmacology, and modulation of human, neuronal L-type (alpha(1D), Ca(V)1.3) voltage-dependent calcium currents". Journal of Neurophysiology. 85 (2): 816–827. doi:10.1152/jn.2001.85.2.816. PMID   11160515. S2CID   147295966.
• Strausberg RL, Feingold EA, Grouse LH (Dec 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–16903. Bibcode:2002PNAS...9916899M. doi: 10.1073/pnas.242603899 . PMC   139241 . PMID   12477932.
• Hillier LW, Fulton RS, Fulton LA (Jul 2003). "The DNA sequence of human chromosome 7". Nature. 424 (6945): 157–164. Bibcode:2003Natur.424..157H. doi: 10.1038/nature01782 . PMID   12853948.
• Stotz SC, Barr W, McRory JE (Jan 2004). "Several structural domains contribute to the regulation of N-type calcium channel inactivation by the beta 3 subunit". The Journal of Biological Chemistry. 279 (5): 3793–3800. doi: 10.1074/jbc.M308991200 . PMID   14602720.
• Liu T, Qian WJ, Gritsenko MA (2006). "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry". Journal of Proteome Research. 4 (6): 2070–2080. doi:10.1021/pr0502065. PMC   1850943 . PMID   16335952.
• Antzelevitch C, Pollevick GD, Cordeiro JM (Jan 2007). "Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death". Circulation. 115 (4): 442–449. doi:10.1161/CIRCULATIONAHA.106.668392. PMC   1952683 . PMID   17224476.
• Chaudhuri D, Issa JB, Yue DT (May 2007). "Elementary mechanisms producing facilitation of Cav2.1 (P/Q-type) channels". The Journal of General Physiology. 129 (5): 385–401. doi:10.1085/jgp.200709749. PMC   2154375 . PMID   17438119.

External links

• CACNA2D1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human CACNA2D1 genome location and CACNA2D1 gene details page in the UCSC Genome Browser .

This article incorporates text from the United States National Library of Medicine, which is in the public domain.