Cav1.3

CACNA1D
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3LV3
Identifiers
Aliases	CACNA1D, CACH3, CACN4, CACNL1A2, CCHL1A2, Cav1.3, PASNA, SANDD, calcium voltage-gated channel subunit alpha1 D
External IDs	OMIM: 114206; MGI: 88293; HomoloGene: 578; GeneCards: CACNA1D; OMA:CACNA1D - orthologs
Gene location (Human) Chr. Chromosome 3 (human) Band 3p21.1 Start 53,328,963 bp End 53,813,733 bp
Gene location (Mouse) Chr. Chromosome 14 (mouse) Band 14 A3- B|14 18.43 cM Start 29,761,896 bp End 30,213,412 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in buccal mucosa cell right lung sural nerve right adrenal gland islet of Langerhans right adrenal cortex left adrenal cortex pituitary gland right uterine tube testicle Top expressed in pituitary gland superior frontal gyrus substantia nigra utricle islet of Langerhans primary visual cortex pineal gland stria vascularis suprachiasmatic nucleus vas deferens More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding voltage-gated ion channel activity high voltage-gated calcium channel activity ion channel activity voltage-gated calcium channel activity involved in cardiac muscle cell action potential alpha-actinin binding ankyrin binding voltage-gated calcium channel activity voltage-gated calcium channel activity involved SA node cell action potential calcium channel activity voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels Cellular component voltage-gated calcium channel complex L-type voltage-gated calcium channel complex integral component of membrane membrane plasma membrane Z discdkac cochlear hair cell ribbon synapse integral component of presynaptic active zone membrane Biological process regulation of atrial cardiac muscle cell membrane repolarization regulation of insulin secretion adenylate cyclase-modulating G protein-coupled receptor signaling pathway calcium ion import regulation of ion transmembrane transport ion transport calcium ion transmembrane transport transmembrane transport regulation of potassium ion transmembrane transporter activity membrane depolarization during cardiac muscle cell action potential regulation of potassium ion transmembrane transport calcium ion transport positive regulation of calcium ion transport hearing cardiac muscle cell action potential involved in contraction membrane depolarization during SA node cell action potential regulation of heart rate by cardiac conduction positive regulation of presynaptic cytosolic calcium concentration induction of synaptic vesicle exocytosis by positive regulation of presynaptic cytosolic calcium ion concentration positive regulation of adenylate cyclase activity cardiac conduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 776 12289 Ensembl ENSG00000157388 ENSMUSG00000015968 UniProt Q01668 Q99246 RefSeq (mRNA) NM_000720 NM_001128839 NM_001128840 NM_001083616 NM_028981 NM_001302637 RefSeq (protein) NP_000711 NP_001122311 NP_001122312 NP_001077085 NP_001289566 NP_083257 Location (UCSC) Chr 3: 53.33 – 53.81 Mb Chr 14: 29.76 – 30.21 Mb PubMed search
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Calcium channel, voltage-dependent, L type, alpha 1D subunit (also known as Ca_v1.3) is a protein that in humans is encoded by the CACNA1D gene. Ca_v1.3 channels belong to the Ca_v1 family, which form L-type calcium currents and are sensitive to selective inhibition by dihydropyridines (DHP).

Structure and function

Schematic representation of the alpha subunit of VDCCs showing the four homologous domains, each with six transmembrane subunits. P-loops are highlighted red, S4 subunits are marked with a plus indicative of positive charge.

Voltage-dependent calcium channels (VDCC) are selectively permeable to calcium ions, mediating the movement of these ions in and out of excitable cells. At resting potential, these channels are closed, but when the membrane potential is depolarised these channels open. The influx of calcium ions into the cell can initiate a myriad of calcium-dependent processes including muscle contraction, gene expression, and secretion. Calcium-dependent processes can be halted by lowering intracellular calcium levels, which, for example, can be accomplished by calcium pumps.

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 Ca_v1.3 channels, the α1 subunit is α1D. This subunit differentiates Ca_v1.3 channels from other members of the Ca_v1 family, such as the predominant and better-studied Ca_v1.2, which has an α1C subunit. The significance of the α1 subunit also means that it is the primary target for calcium-channel blockers such as dihydropyridines. The remaining β, α2δ and γ subunits have auxiliary functions.

The α1 subunit has four homologous domains, each with six transmembrane segments. Within each homologous domain, the fourth transmembrane segment (S4) is positively charged, as opposed to the other five hydrophobic segments. This characteristic enables S4 to function as the voltage-sensor. Alpha-1D subunits belong to the Ca_v1 family, which is characterised by L-type calcium currents. Specifically, α1D subunits confer low-voltage activation and slowly inactivating Ca²⁺ currents, ideal for particular physiological functions such as neurotransmitter release in cochlea inner hair cells.

The biophysical properties of Ca_v1.3 channels are closely regulated by a C-terminal modulatory domain (CTM), which affects both the voltage dependence of activation and Ca²⁺ dependent inactivation. Ca_v1.3 have a low affinity for DHP and activate at sub-threshold membrane potentials, making them ideal for a role in cardiac pacemaking.

Regulation

Alternative splicing

Post-transcriptional alternative splicing of Ca_v1.3 is an extensive and vital regulatory mechanism. Alternative splicing can significantly affect the gating properties of the channel. Comparable to alternative splicing of Ca_v1.2 transcripts, which confers functional specificity, it has recently been discovered that alternative splicing, particularly in the C-terminus, affects the pharmacological properties of Ca_v1.3. Strikingly, up to 8-fold differences in dihydropyridine sensitivity between alternatively spliced isoforms have been reported.

Negative feedback

Ca_v1.3 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 Ca_v1.3 to induce calcium-dependent inactivation (CDI). Recently, it has been shown that RNA editing of Ca_v1.3 transcripts is essential for CDI. 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

Ca_v1.3 channels are widely expressed in humans. Notably, their expression predominates in cochlea inner hair cells (IHCs). Ca_v1.3 have been shown through patch clamp experiments to be essential for normal IHC development and synaptic transmission. Therefore, Ca_v1.3 are required for proper hearing.

Chromaffin cells

Ca_v1.3 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 Ca_v1.3. Catecholamines have many systemic effects on multiple organs. In addition, L-type channels are responsible for exocytosis in these cells.

Neurodegeneration

Parkinson's disease is the second most common neurodegenerative disease, in which the death of dopamine-producing cells in the substantia nigra of the midbrain leads to impaired motor function, perhaps best characterised by tremor. Recent evidence suggests that L-type Ca_v1.3 Ca²⁺ channels contribute to the death of dopaminergic neurones in patients with Parkinson's disease. The basal activity of these neurones is also dependent on L-type Ca²⁺ channels, such as Ca_v1.3. Continuous pacemaking activity drives permanent intracellular dendritic and somatic calcium transients, which appears to make the dopaminergic substantia nigra neurones vulnerable to stressors that contribute to their death. Therefore inhibition of L-type channels, in particular Ca_v1.3 is protective against the pathogenesis of Parkinson's in some animal models. A clinical phase III trial (STEADY-PD III Archived 2019-04-07 at the Wayback Machine) testing this hypothesis in patients with early Parkinsons's failed to show efficacy in slowing the progression of Parkinson's.

Inhibition of Ca_v1.3 can be achieved using calcium channel blockers, such as dihydropyridines (DHPs). These drugs are used since decades to treat arterial hypertension and angina. This is due to their potent vasorelaxant properties, which are mediated by the inhibition of Ca_v1.2 L-type calcium channels in arterial smooth muscle. Therefore, hypotensive reactions (and leg edema) are regarded dose-limiting side effects when using DHPs for inhibiting Ca_v1.3 channel in the brain. In the face of this issue, attempts have been made to discover selective Ca_v1.3 channel blockers. One candidate has been claimed to be a potent and highly selective inhibitor of Ca_v1.3. This compound, 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione was therefore put forward as a candidate for the future treatment of Parkinson's. However, its selectivity and potency could not be confirmed in two independent studies from two other groups. One of them even reported gating changes induced by this drug., which indicate channel activating rather than blocking effects.

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. 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 somatic mutations in conserved regions within the channel's activation gate of its pore-forming α1-subunit (CACNA1D) cause excessive aldosterone production in aldosterone-producing adenomas (APA) resulting in primary aldosteronism, which causes treatment - resistant arterial hypertension. These mutations allow increased Ca²⁺ influx through Cav1.3, which in turn triggers Ca²⁺ - dependent aldosterone production. The number of validated APA mutations is constantly growing. In rare cases, APA mutations have also been found as germline mutations in individuals with neurodevelopmental disorders of different severity, including autism spectrum disorder.

See also

• Calcium channel

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. doi:10.1016/0896-6273(92)90109-Q. PMID 1309651. 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. Bibcode:1992PNAS...89..584S. doi:10.1073/pnas.89.2.584. PMC 48283. 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. doi:10.1016/0888-7543(92)90078-7. 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. doi:10.1016/0888-7543(91)90014-6. 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. Bibcode:1991Natur.350..398M. doi:10.1038/350398a0. PMID 1849233. 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. doi:10.1006/geno.1995.1048. 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. doi:10.1016/0169-328X(96)80478-5. 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. doi:10.1073/pnas.96.18.10164. PMC 17860. 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. doi:10.1152/jn.2001.85.2.816. PMID 11160515. 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. doi:10.1096/fj.00-0188com. 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. doi:10.1126/science.293.5527.98. 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. doi:10.1172/JCI13310. PMC 200955. 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. doi:10.1074/jbc.M401481200. 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. doi:10.1161/CIRCULATIONAHA.104.517326. 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. doi:10.1152/ajpheart.00095.2006. PMID 16973824. 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. doi:10.1016/j.cell.2006.09.026. PMID 17081983. 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.