Cav1.3

Calcium channel, voltage-dependent, L type, alpha 1D subunit

PDB rendering based on 2be6.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
3LV3

Identifiers

Symbols

CACNA1D ; CACH3; CACN4; CACNL1A2; CCHL1A2; Cav1.3; PASNA; SANDD

External IDs

OMIM: 114206 MGI: 88293 HomoloGene: 578 IUPHAR: 530 ChEMBL: 4138 GeneCards: CACNA1D Gene

Gene ontology
Molecular function	• voltage-gated calcium channel activity • high voltage-gated calcium channel activity • ankyrin binding • metal ion binding • alpha-actinin binding • voltage-gated calcium channel activity involved in cardiac muscle cell action potential • voltage-gated calcium channel activity involved SA node cell action potential
Cellular component	• plasma membrane • voltage-gated calcium channel complex • Z disc
Biological process	• energy reserve metabolic process • calcium ion transport • adenylate cyclase-modulating G-protein coupled receptor signaling pathway • axon guidance • sensory perception of sound • ion transmembrane transport • small molecule metabolic process • regulation of insulin secretion • positive regulation of calcium ion transport • regulation of atrial cardiac muscle cell membrane repolarization • calcium ion import • calcium ion transmembrane transport • membrane depolarization during cardiac muscle cell action potential • membrane depolarization during SA node cell action potential • regulation of heart rate by cardiac conduction • regulation of potassium ion transmembrane transporter activity • regulation of potassium ion transmembrane transport
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

776

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 3:
53.49 – 53.81 Mb

Chr 14:
30.04 – 30.49 Mb

PubMed search

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.^[1] 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.^[2]

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.^[3] 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.^[4]

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,^[5] 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.^[6]

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.^[7] 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 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.^[8] 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.^[9]

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.^[4] The basal activity of these neurones is highly dependent on L-type Ca²⁺ channels, such as Ca_v1.3, and it suggested that the pacemaking activity makes the dopaminergic neurones vulnerable to stressors that contribute to their death. Results suggest that inhibition of Ca_v1.3 is protective against the pathogenesis of Parkinson's.^[4]

Inhibition of Ca_v1.3 can be achieved using blockers such as DHP. However, the broad action of DHP, which also affects Ca_v1.2, has limited therapeutic use as it would disturb a wide range of neurological processes to the detriment of the patient. In the face of this issue, a potent and highly selective Ca_v1.3 antagonist 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione was recently identified and put forward as a candidate for the future treatment of Parkinson's.^[10]

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.^[11] 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

Mutations in the S6 segment of CACNA1D are associated with primary aldosteronism, which causes arterial hypertension. Alterations to the Gly403 residue result in channel activation at less depolarised potentials and impaired channel inactivation. This leads to increased Ca²⁺ influx, which in turn triggers aldosterone production.^[12]

References

↑ "Entrez Gene: CACNA1D calcium channel, voltage-dependent, L type, alpha 1D subunit".
↑ Brown BL, Walker SW, Tomlinson S (Aug 1985). "Calcium calmodulin and hormone secretion". Clinical Endocrinology 23 (2): 201–18. doi:10.1111/j.1365-2265.1985.tb00216.x. PMID 2996810.
↑ Lieb A, Scharinger A, Sartori S, Sinnegger-Brauns MJ, Striessnig J (2012). "Structural determinants of CaV1.3 L-type calcium channel gating". Channels 6 (3): 197–205. doi:10.4161/chan.21002. PMID 22760075.
1 2 3 Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, Meredith GE, Surmeier DJ (Jun 2007). "'Rejuvenation' protects neurons in mouse models of Parkinson's disease". Nature 447 (7148): 1081–6. doi:10.1038/nature05865. PMID 17558391.
↑ Liao P, Yu D, Lu S, Tang Z, Liang MC, Zeng S, Lin W, Soong TW (Nov 2004). "Smooth muscle-selective alternatively spliced exon generates functional variation in Cav1.2 calcium channels". The Journal of Biological Chemistry 279 (48): 50329–35. doi:10.1074/jbc.m409436200. PMID 15381693.
↑ Huang H, Yu D, Soong TW (Oct 2013). "C-terminal alternative splicing of CaV1.3 channels distinctively modulates their dihydropyridine sensitivity". Molecular Pharmacology 84 (4): 643–53. doi:10.1124/mol.113.087155. PMID 23924992.
↑ Bazzazi H, Ben Johny M, Adams PJ, Soong TW, Yue DT (Oct 2013). "Continuously tunable Ca(2+) regulation of RNA-edited CaV1.3 channels". Cell Reports 5 (2): 367–77. doi:10.1016/j.celrep.2013.09.006. PMID 24120865.
↑ Brandt A, Striessnig J, Moser T (Nov 2003). "CaV1.3 channels are essential for development and presynaptic activity of cochlear inner hair cells". The Journal of Neuroscience 23 (34): 10832–40. PMID 14645476.
↑ Vandael DH, Mahapatra S, Calorio C, Marcantoni A, Carbone E (Jul 2013). "Cav1.3 and Cav1.2 channels of adrenal chromaffin cells: emerging views on cAMP/cGMP-mediated phosphorylation and role in pacemaking". Biochimica et Biophysica Acta 1828 (7): 1608–18. doi:10.1016/j.bbamem.2012.11.013. PMID 23159773.
↑ Kang S, Cooper G, Dunne SF, Dusel B, Luan CH, Surmeier DJ, Silverman RB (2012). "CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease". Nature Communications 3: 1146. doi:10.1038/ncomms2149. PMID 23093183.
↑ Chen R, Zeng X, Zhang R, Huang J, Kuang X, Yang J, Liu J, Tawfik O, Thrasher JB, Li B (Jul 2014). "Cav1.3 channel α1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers". Urologic Oncology 32 (5): 524–36. doi:10.1016/j.urolonc.2013.05.011. PMID 24054868.
↑ Scholl UI, Goh G, Stölting G, de Oliveira RC, Choi M, Overton JD, Fonseca AL, Korah R, Starker LF, Kunstman JW, Prasad ML, Hartung EA, Mauras N, Benson MR, Brady T, Shapiro JR, Loring E, Nelson-Williams C, Libutti SK, Mane S, Hellman P, Westin G, Åkerström G, Björklund P, Carling T, Fahlke C, Hidalgo P, Lifton RP (Sep 2013). "Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism". Nature Genetics 45 (9): 1050–4. doi:10.1038/ng.2695. PMID 23913001.

External links

CACNA1D protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery

2be6: 2.0 A crystal structure of the CaV1.2 IQ domain-Ca/CaM complex

Membrane transport protein: ion channels (TC 1A)

Ca²⁺: Calcium channel

Ligand-gated	Inositol trisphosphate receptor 1 2 3 Ryanodine receptor 1 2 3

Voltage-gated	L-type/Ca_vα 1.1 1.2 1.3 1.4 N-type/Ca_vα2.2 P-type/Ca_vα 2.1 Q-type/Ca_vα2.1 R-type/Ca_vα2.3 T-type/Ca_vα 3.1 3.2 3.3 α₂δ-subunits 1 2 β-subunits β1 β2 β3 β4 γ-subunits γ1 γ2 γ3 γ4 Cation channels of sperm 1 2 3 4 Two-pore channel 1 2

Na⁺: Sodium channel

Constitutively active	Epithelial sodium channel α β γ δ

Proton-gated	Amiloride-sensitive cation channel 1 2 3 4

Voltage-gated	Na_vα 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 7A Na_vβ 1 2 3 4

K⁺: Potassium channel

Calcium-activated	BK channel α1 β1 β2 β3 β4 SK channel SK1 SK2 SK3 IK channel IK1 K_Ca 1.1 2.1 2.2 2.3 3.1 4.1 4.2 5.1

Inward-rectifier	K_ATP K_ir 1.1 2.1 2.2 2.3 2.4 2.6 GIRK/K_ir 3.1 3.2 3.3 3.4 K_ir 4.1 4.2 5.1 6.1 6.2 7.1

Tandem pore domain	K2P 1 2 3 4 5 6 7 9 10 12 13 15 16 17 18

Voltage-gated	K_vα1-6 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 2.1 2.2 3.1 3.2 3.3 3.4 4.1 4.2 4.3 5.1 6.1 6.2 6.3 6.4 K_vα7-12 7.1 7.2 7.3 7.4 7.5 8.1 8.2 9.1 9.2 9.3 10.1 10.2 11.1/hERG 11.2 11.3 12.1 12.2 12.3 K_vβ 1 2 3 KCNIP 1 2 3 4 minK/ISK minK/ISK-like MiRP 1 2 3 Shaker gene

Miscellaneous

Cl⁻: Chloride channel	Calcium-activated chloride channels Anoctamin ANO1 Bestrophin 1 2 Chloride Channel Accessory 1 2 3 4 CFTR CLCN 1 2 3 4 5 6 7 KA KB CLIC 1 2 3 4 5 6 L1 CLNS 1A 1B

H⁺: Proton channel	HVCN1

M⁺: CNG cation channel	α 1 2 3 4 β 1 2 3 HCN FC 1 2 3 4

M⁺: TRP cation channel	TRPA (1) TRPC 1 2 3 4 4AP 5 6 7 TRPM 1 2 3 4 5 6 7 8 TRPML 1 2 3 TRPN TRPP 1 2 TRPV 1 2 3 4 5 6

H₂O (+ solutes): Porin	Aquaporin 0 1 2 3 4 5 6 7 8 9 Voltage-dependent anion channel 1 2 3 General bacterial porin family

Cytoplasm: Gap junction	Connexin: A GJA1 GJA3 GJA4 GJA5 GJA8 GJA9 GJA10 B GJB1 GJB2 GJB3 GJB4 GJB5 GJB6 GJB7 C GJC1 GJC2 GJC3 D GJD2 GJD3 GJD4) Innexin

By gating mechanism

Ion channel class	Ligand-gated Light-gated Voltage-gated Stretch-activated

see also disorders

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

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