Cav1.3

CACNA1D
Protein CACNA1D PDB 2be6.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CACNA1D, CACH3, CACN4, CACNL1A2, CCHL1A2, Cav1.3, PASNA, SANDD, calcium voltage-gated channel subunit alpha1 D
External IDs MGI: 88293 HomoloGene: 578 GeneCards: CACNA1D
Gene location (Human)
Chromosome 3 (human)
Chr. Chromosome 3 (human)[1]
Chromosome 3 (human)

Genomic location for CACNA1D
Genomic location for CACNA1D
Band 3p21.1 Start 53,328,963 bp[1]
End 53,813,733 bp[1]
RNA expression pattern
PBB GE CACNA1D 207998 s at fs.png

PBB GE CACNA1D 210108 at fs.png

More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
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: 30.04 – 30.49 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Calcium channel, voltage-dependent, L type, alpha 1D subunit (also known as Cav1.3) is a protein that in humans is encoded by the CACNA1D gene.[5] Cav1.3 channels belong to the Cav1 family, which form L-type calcium currents and are sensitive to selective inhibition by dihydropyridines (DHP).

Structure and function[edit]

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.[6]

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 Cav1.2, 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 Cav1 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 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[edit]

Alternative splicing[edit]

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[edit]

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[edit]

Hearing[edit]

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[edit]

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[edit]

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 Cav1.3 Ca2+ channels contribute to the death of dopaminergic neurones in patients with Parkinson’s disease.[8] The basal activity of these neurones is also dependent on L-type Ca2+ channels, such as Cav1.3. Continuous pacemaking activity drives permanent intracellular dendritic and somatic calcium transiennts, 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 Cav1.3 is protective against the pathogenesis of Parkinson’s in some animal models.[8][19] A clinical phase III trial (STEADY-PD III) testing this hypothesis in patients with early Parkinsons’s is underway and its results will be released in May 2019.

Inhibition of Cav1.3 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 Cav1.2 L-type calcium channels in arterial smooth muscle.[15] Therefore, hypotensive reactions (and leg edema) are regarded dose-limiting side effects when using DHPs for inhibiting Cav1.3 channel in the brain.[20] In the face of this issue, attempts have been made to discover selective Cav1.3 channel blockers. One candidate has been claimed to be a potent and highly selective inhibitor of Cav1.3. 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.[21] However, its selectivtiy and potency could not be confirmed in two independent studies from two other groups.[22] One of them even reported gating changes induced by this drug., which indicate channel activating rather than blocking effects.[23]

Prostate cancer[edit]

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.[24] 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[edit]

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.[25][26] The number of validated APA mutations is constantly growing.[27] In rare cases, APA mutations have also been found as germline mutations in individuals with neurodevelopmental disorders of different severity, including autism spectrum disorder.[25][27][28]

See also[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000157388Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015968Ensembl, May 2017
  3. ^ “Human PubMed Reference:”.
  4. ^ “Mouse PubMed Reference:”.
  5. ^ “Entrez Gene: CACNA1D calcium channel, voltage-dependent, L type, alpha 1D subunit”.
  6. ^ Brown BL, Walker SW, Tomlinson S (August 1985). “Calcium calmodulin and hormone secretion”. Clinical Endocrinology. 23 (2): 201–18. doi:10.1111/j.1365-2265.1985.tb00216.x. PMID 2996810.
  7. ^ 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. PMC 3431584. PMID 22760075.
  8. ^ a b c Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, Meredith GE, Surmeier DJ (June 2007). “Rejuvenation’ protects neurons in mouse models of Parkinson’s disease”. Nature. 447 (7148): 1081–6. Bibcode:2007Natur.447.1081C. doi:10.1038/nature05865. PMID 17558391.
  9. ^ Liao P, Yu D, Lu S, Tang Z, Liang MC, Zeng S, Lin W, Soong TW (November 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.
  10. ^ Singh A, Gebhart M, Fritsch R, Sinnegger-Brauns MJ, Poggiani C, Hoda JC, Engel J, Romanin C, Striessnig J, Koschak A (July 2008). “Modulation of voltage- and Ca2+-dependent gating of CaV1.3 L-type calcium channels by alternative splicing of a C-terminal regulatory domain”. The Journal of Biological Chemistry. 283 (30): 20733–44. doi:10.1074/jbc.M802254200. PMC 2475692. PMID 18482979.
  11. ^ Tan BZ, Jiang F, Tan MY, Yu D, Huang H, Shen Y, Soong TW (December 2011). “Functional characterization of alternative splicing in the C terminus of L-type CaV1.3 channels”. The Journal of Biological Chemistry. 286 (49): 42725–35. doi:10.1074/jbc.M111.265207. PMC 3234967. PMID 21998309.
  12. ^ Huang H, Yu D, Soong TW (October 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.
  13. ^ Ortner NJ, Bock G, Dougalis A, Kharitonova M, Duda J, Hess S, Tuluc P, Pomberger T, Stefanova N, Pitterl F, Ciossek T, Oberacher H, Draheim HJ, Kloppenburg P, Liss B, Striessnig J (July 2017). “2+ Channels during Substantia Nigra Dopamine Neuron-Like Activity: Implications for Neuroprotection in Parkinson’s Disease”. The Journal of Neuroscience. 37 (28): 6761–6777. doi:10.1523/JNEUROSCI.2946-16.2017. PMID 28592699.
  14. ^ Bazzazi H, Ben Johny M, Adams PJ, Soong TW, Yue DT (October 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. PMC 4349392. PMID 24120865.
  15. ^ a b Zamponi GW, Striessnig J, Koschak A, Dolphin AC (October 2015). “The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential”. Pharmacological Reviews. 67 (4): 821–70. doi:10.1124/pr.114.009654. PMC 4630564. PMID 26362469.
  16. ^ Brandt A, Striessnig J, Moser T (November 2003). “CaV1.3 channels are essential for development and presynaptic activity of cochlear inner hair cells”. The Journal of Neuroscience. 23 (34): 10832–40. doi:10.1523/JNEUROSCI.23-34-10832.2003. PMID 14645476.
  17. ^ Platzer J, Engel J, Schrott-Fischer A, Stephan K, Bova S, Chen H, Zheng H, Striessnig J (July 2000). “Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels”. Cell. 102 (1): 89–97. doi:10.1016/S0092-8674(00)00013-1. PMID 10929716.
  18. ^ Vandael DH, Mahapatra S, Calorio C, Marcantoni A, Carbone E (July 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.
  19. ^ Liss B, Striessnig J (January 2019). “The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson’s Disease”. Annual Review of Pharmacology and Toxicology. 59 (1): 263–289. doi:10.1146/annurev-pharmtox-010818-021214. PMID 30625283.
  20. ^ “Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson’s disease (STEADY-PD)”. Movement Disorders. 28 (13): 1823–31. November 2013. doi:10.1002/mds.25639. PMID 24123224.
  21. ^ 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.
  22. ^ Huang H, Ng CY, Yu D, Zhai J, Lam Y, Soong TW (July 2014). “Modest CaV1.342-selective inhibition by compound 8 is β-subunit dependent”. Nature Communications. 5: 4481. doi:10.1038/ncomms5481. PMC 4124865. PMID 25057870.Ortner NJ, Bock G, Vandael DH, Mauersberger R, Draheim HJ, Gust R, Carbone E, Tuluc P, Striessnig J (June 2014). “Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators”. Nature Communications. 5: 3897. doi:10.1038/ncomms4897. PMC 4083433. PMID 24941892.
  23. ^ Ortner NJ, Bock G, Vandael DH, Mauersberger R, Draheim HJ, Gust R, Carbone E, Tuluc P, Striessnig J (June 2014). “Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators”. Nature Communications. 5: 3897. doi:10.1038/ncomms4897. PMC 4083433. PMID 24941892.
  24. ^ Chen R, Zeng X, Zhang R, Huang J, Kuang X, Yang J, Liu J, Tawfik O, Thrasher JB, Li B (July 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.
  25. ^ a b 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 (September 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. PMC 3876926. PMID 23913001.
  26. ^ Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Küsters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ (September 2013). “Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension”. Nature Genetics. 45 (9): 1055–60. doi:10.1038/ng.2716. PMID 23913004.
  27. ^ a b Pinggera A, Striessnig J (October 2016). “2+ channel dysfunction in CNS disorders”. The Journal of Physiology. 594 (20): 5839–5849. doi:10.1113/JP270672. PMC 4823145. PMID 26842699.
  28. ^ Pinggera A, Negro G, Tuluc P, Brown MJ, Lieb A, Striessnig J (January 2018). “2+ channels”. Channels. 12 (1): 388–402. doi:10.1080/19336950.2018.1546518. PMC 6287693. PMID 30465465.

Further reading[edit]

External links[edit]

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