Cav1.3

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Calcium channel, voltage-dependent, L type, alpha 1D subunit
Protein CACNA1D PDB 2be6.png
PDB rendering based on 2be6.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CACNA1D ; CACH3; CACN4; CACNL1A2; CCHL1A2; Cav1.3; PASNA; SANDD
External IDs OMIM114206 MGI88293 HomoloGene578 IUPHAR: 530 ChEMBL: 4138 GeneCards: CACNA1D Gene
RNA expression pattern
PBB GE CACNA1D 210108 at tn.png
PBB GE CACNA1D 207998 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 776 12289
Ensembl ENSG00000157388 ENSMUSG00000015968
UniProt Q01668 Q99246
RefSeq (mRNA) NM_000720 NM_001083616
RefSeq (protein) NP_000711 NP_001077085
Location (UCSC) Chr 3:
53.53 – 53.85 Mb
Chr 14:
30.04 – 30.49 Mb
PubMed search [1] [2]

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.[1] 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.[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 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.[3] Cav1.3 have a low affinity for DHP and activate at sub-threshold membrane potentials, making them ideal for a role in cardiac pacemaking.[4]

Regulation[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,[5] it has recently been discovered that alternative splicing, particularly in the C-terminus, affects the pharmacological properties of Cav1.3. Strikingly, up to 8-fold differences in dihydropyridine sensitivity between alternatively spliced isoforms have been reported.[6]

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.[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[edit]

Hearing[edit]

Cav1.3 channels are widely expressed in humans. Notably, their expression predominates cochlea inner hair cells (IHCs). Cav1.3 have been shown through patch clamp experiments to be essential for normal IHC development and synaptic transmission.[8] Therefore, Cav1.3 are required for proper hearing.

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.[9]

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.[4] The basal activity of these neurones is highly dependent on L-type Ca2+ channels, such as Cav1.3, and it suggested that the pacemaking activity makes the dopaminergic neurones vulnerable to stressors that contribute to their death. Results suggest that inhibition of Cav1.3 is protective against the pathogenesis of Parkinson's.[4]

Inhibition of Cav1.3 can be achieved using blockers such as DHP. However, the broad action of DHP, which also affects Cav1.2, 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 Cav1.3 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[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.[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[edit]

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]

See also[edit]

References[edit]

  1. ^ "Entrez Gene: CACNA1D calcium channel, voltage-dependent, L type, alpha 1D subunit". 
  2. ^ Brown, B. L., S. W. Walker, and S. Tomlinson et al. (1985). "Calcium calmodulin and hormone secretion". Clinical endocrinology 23: 201–218. doi:10.1111/j.1365-2265.1985.tb00216.x. 
  3. ^ Lieb, A., Scharinger, A., Sartori, S. et al. (2012). "Structural determinants of CaV1. 3 L-type calcium channel gating". Channels 6(3): 197–205. 
  4. ^ a b c Chan, C. S., Guzman, J. N., Ilijic, E. et al. (2007). "‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease". Nature. 447(7148): 1081–1086. 
  5. ^ Liao, P., Yu, D., Lu, S. et al. (2004). "Smooth muscle-selective alternatively spliced exon generates functional variation in Cav1. 2 calcium channels". Journal of Biological Chemistry. 279(48): 50329–50335. 
  6. ^ Huang, H., Yu, D., & Soong, T. W. et al. (2013). "C-terminal alternative splicing of CaV1. 3 channels distinctively modulates their dihydropyridine sensitivity.". Molecular pharmacology. 84(4): 643–653. 
  7. ^ Bazzazi, H., Johny, M. B., Adams, P. J. et al. (2013). "Continously unable Ca 2+ regulation of RNA-edited CaV1.3 channels". Cell reports 5(2): 367–377. 
  8. ^ Brandt, A., Striessnig, J., and Moser, T. (2003). "CaV1. 3 channels are essential for development and presynaptic activity of cochlear inner hair cells". The Journal of Neuroscience. 23(34): 10832–10840. 
  9. ^ Vandael, D. H. F., Mahapatra, S., Calorio, C. et al. (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 (BBA)-Biomembranes. 1828(7): 1608–1618. 
  10. ^ Kang, S., Cooper, G., Dunne, S. F. et al. (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. 
  11. ^ Chen, R., Zeng, X., Zhang, R. et al. (2014). "Ca v 1.3 channel α 1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers". Urologic Oncology: Seminars and Original Investigations. 32(5): 524–536. 
  12. ^ Scholl, U. I., Goh, G., Stölting, G et al. (2013). "Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism". Nature genetics. 45(9): 1050–1054. doi:10.1038/ng.2695. 


Further reading[edit]

External links[edit]

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