Cav1.3
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Location (UCSC) | Chr 3: 53.33 – 53.81 Mb | Chr 14: 29.76 – 30.21 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Calcium channel, voltage-dependent, L type, alpha 1D subunit (also known as Cav1.3) is a
Structure and function
Voltage-dependent calcium channels are multi-proteins composed of α1, β, α2δ and γ subunits. The major subunit is α1, which forms the selectivity pore, voltage-sensor and gating apparatus of VDCCs. In Cav1.3 channels, the α1 subunit is α1D. This subunit differentiates Cav1.3 channels from other members of the Cav1 family, such as the predominant and better-studied
The α1 subunit has four
The biophysical properties of Cav1.3 channels are closely regulated by a C-terminal modulatory domain (CTM), which affects both the voltage dependence of activation and Ca2+ dependent inactivation.[7] Cav1.3 have a low affinity for DHP and activate at sub-threshold membrane potentials, making them ideal for a role in cardiac pacemaking.[8]
Regulation
Alternative splicing
Post-transcriptional alternative splicing of Cav1.3 is an extensive and vital regulatory mechanism. Alternative splicing can significantly affect the gating properties of the channel. Comparable to alternative splicing of Cav1.2 transcripts, which confers functional specificity,[9] it has recently been discovered that alternative splicing, particularly in the C-terminus, affects the pharmacological properties of Cav1.3.[10][11] Strikingly, up to 8-fold differences in dihydropyridine sensitivity between alternatively spliced isoforms have been reported.[12][13]
Negative feedback
Cav1.3 channels are regulated by negative feedback to achieve Ca2+ homeostasis. Calcium ions are a critical second messenger, intrinsic to intracellular signal transduction. Extracellular calcium levels are approximated to be 12000-fold greater than intracellular levels. During calcium-dependent processes, the intracellular level of calcium rises by up to 100-fold. It is vitally important to regulate this calcium gradient, not least because high levels of calcium are toxic to the cell, and can induce apoptosis.
Ca2+-bound calmodulin (CaM) interacts with Cav1.3 to induce calcium-dependent inactivation (CDI). Recently, it has been shown that RNA editing of Cav1.3 transcripts is essential for CDI.[14] Contrary to expectation, RNA editing does not simply attenuate the binding of CaM, but weakens the pre-binding of Ca2+-free calmodulin (apoCaM) to channels. The upshot is that CDI is continuously tuneable by changes in levels of CaM.
Clinical significance
Hearing
Cav1.3 channels are widely expressed in humans.[15] Notably, their expression predominates in cochlea inner hair cells (IHCs). Cav1.3 have been shown through patch clamp experiments to be essential for normal IHC development and synaptic transmission.[16] Therefore, Cav1.3 are required for proper hearing.[17]
Chromaffin cells
Cav1.3 are densely expressed in chromaffin cells. The low-voltage activation and slow inactivation of these channels makes them ideal for controlling excitability in these cells. Catecholamine secretion from chromaffin cells is particularly sensitive to L-type currents, associated with Cav1.3. Catecholamines have many systemic effects on multiple organs. In addition, L-type channels are responsible for exocytosis in these cells.[18]
Neurodegeneration
Inhibition of Cav1.3 can be achieved using calcium channel blockers, such as
Prostate cancer
Recent evidence from immunostaining experiments shows that CACNA1D is highly expressed in prostate cancers compared with benign prostate tissues. Blocking L-type channels or knocking down gene expression of CACNA1D significantly suppressed cell-growth in prostate cancer cells.[25] It is important to recognise that this association does not represent a causal link between high levels of α1D protein and prostate cancer. Further investigation is needed to explore the role of CACNA1D gene overexpression in prostate cancer cell growth.
Aldosteronism
De novo
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000157388 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015968 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: CACNA1D calcium channel, voltage-dependent, L type, alpha 1D subunit".
- S2CID 45017291.
- PMID 22760075.
- ^ S2CID 4429534.
- PMID 15381693.
- PMID 18482979.
- PMID 21998309.
- S2CID 22439331.
- PMID 28592699.
- PMID 24120865.
- ^ PMID 26362469.
- PMID 14645476.
- S2CID 17923472.
- PMID 23159773.
- S2CID 58619079.
- ^ Hoffman M (5 May 2019). "Isradipine Fails to Slow Early Parkinson Disease Progression in Phase 3 Study". NeurologyLive. Retrieved 2019-11-25.
- S2CID 9594193.
- PMID 23093183.
- PMID 24941892.
- PMID 24941892.
- PMID 24054868.
- ^ PMID 23913001.
- S2CID 205347424.
- ^ PMID 26842699.
- PMID 30465465.
Further reading
- Williams ME, Feldman DH, McCue AF, Brenner R, Velicelebi G, Ellis SB, Harpold MM (January 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. S2CID 39341712.
- Seino S, Chen L, Seino M, Blondel O, Takeda J, Johnson JH, Bell GI (January 1992). "Cloning of the alpha 1 subunit of a voltage-dependent calcium channel expressed in pancreatic beta cells". Proceedings of the National Academy of Sciences of the United States of America. 89 (2): 584–8. PMID 1309948.
- Seino S, Yamada Y, Espinosa R, Le Beau MM, Bell GI (August 1992). "Assignment of the gene encoding the alpha 1 subunit of the neuroendocrine/brain-type calcium channel (CACNL1A2) to human chromosome 3, band p14.3". Genomics. 13 (4): 1375–7. PMID 1324226.
- Chin HM, Kozak CA, Kim HL, Mock B, McBride OW (December 1991). "A brain L-type calcium channel alpha 1 subunit gene (CCHL1A2) maps to mouse chromosome 14 and human chromosome 3". Genomics (Submitted manuscript). 11 (4): 914–9. PMID 1664412.
- Mori Y, Friedrich T, Kim MS, Mikami A, Nakai J, Ruth P, Bosse E, Hofmann F, Flockerzi V, Furuichi T (April 1991). "Primary structure and functional expression from complementary DNA of a brain calcium channel". Nature. 350 (6317): 398–402. S2CID 4370532.
- Yamada Y, Masuda K, Li Q, Ihara Y, Kubota A, Miura T, Nakamura K, Fujii Y, Seino S, Seino Y (May 1995). "The structures of the human calcium channel alpha 1 subunit (CACNL1A2) and beta subunit (CACNLB3) genes". Genomics. 27 (2): 312–9. PMID 7557998.
- Puro DG, Hwang JJ, Kwon OJ, Chin H (April 1996). "Characterization of an L-type calcium channel expressed by human retinal Müller (glial) cells". Brain Research. Molecular Brain Research (Submitted manuscript). 37 (1–2): 41–8. PMID 8738134.
- Yang SN, Larsson O, Bränström R, Bertorello AM, Leibiger B, Leibiger IB, Moede T, Köhler M, Meister B, Berggren PO (August 1999). "Syntaxin 1 interacts with the L(D) subtype of voltage-gated Ca(2+) channels in pancreatic beta cells". Proceedings of the National Academy of Sciences of the United States of America. 96 (18): 10164–9. PMID 10468580.
- Bell DC, Butcher AJ, Berrow NS, Page KM, Brust PF, Nesterova A, Stauderman KA, Seabrook GR, Nürnberg B, Dolphin AC (February 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): 816–27. S2CID 147295966.
- Rosenthal R, Thieme H, Strauss O (April 2001). "Fibroblast growth factor receptor 2 (FGFR2) in brain neurons and retinal pigment epithelial cells act via stimulation of neuroendocrine L-type channels (Ca(v)1.3)". FASEB Journal. 15 (6): 970–7. PMID 11292657.
- Davare MA, Avdonin V, Hall DD, Peden EM, Burette A, Weinberg RJ, Horne MC, Hoshi T, Hell JW (July 2001). "A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2". Science. 293 (5527): 98–101. PMID 11441182.
- Namkung Y, Skrypnyk N, Jeong MJ, Lee T, Lee MS, Kim HL, Chin H, Suh PG, Kim SS, Shin HS (October 2001). "Requirement for the L-type Ca(2+) channel alpha(1D) subunit in postnatal pancreatic beta cell generation". The Journal of Clinical Investigation. 108 (7): 1015–22. PMID 11581302.
- Stokes L, Gordon J, Grafton G (May 2004). "Non-voltage-gated L-type Ca2+ channels in human T cells: pharmacology and molecular characterization of the major alpha pore-forming and auxiliary beta-subunits". The Journal of Biological Chemistry. 279 (19): 19566–73. PMID 14981074.
- Qu Y, Baroudi G, Yue Y, Boutjdir M (June 2005). "Novel molecular mechanism involving alpha1D (Cav1.3) L-type calcium channel in autoimmune-associated sinus bradycardia". Circulation. 111 (23): 3034–41. PMID 15939813.
- Baroudi G, Qu Y, Ramadan O, Chahine M, Boutjdir M (October 2006). "Protein kinase C activation inhibits Cav1.3 calcium channel at NH2-terminal serine 81 phosphorylation site". American Journal of Physiology. Heart and Circulatory Physiology. 291 (4): H1614-22. S2CID 863259.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (November 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. S2CID 7827573.
External links
- CACNA1D+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: Q01668 (Voltage-dependent L-type calcium channel subunit alpha-1D) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.