Calcium channel, voltage-dependent, L type, alpha 1D subunit (also known asCav1.3) is aprotein that in humans is encoded by theCACNA1D gene.[5] Cav1.3 channels belong to the Cav1 family, which form L-type calcium currents and are sensitive to selective inhibition bydihydropyridines (DHP).
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 tocalcium ions, mediating the movement of these ions in and out of excitable cells. Atresting potential, these channels are closed, but when the membrane potential isdepolarised these channels open. The influx of calcium ions into the cell can initiate a myriad of calcium-dependent processes includingmuscle contraction,gene expression, andsecretion. Calcium-dependent processes can be halted by lowering intracellular calcium levels, which, for example, can be accomplished bycalcium 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-studiedCav1.2, which has an α1C subunit. The significance of the α1 subunit also means that it is the primary target for calcium-channel blockers such asdihydropyridines. The remaining β, α2δ and γ subunits have auxiliary functions.
The α1 subunit has fourhomologous domains, each with six transmembrane segments. Within each homologous domain, the fourth transmembrane segment (S4) is positively charged, as opposed to the other fivehydrophobic 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 asneurotransmitter release incochlea 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 incardiac pacemaking.[8]
Post-transcriptionalalternative 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]
Cav1.3 channels are regulated bynegative feedback to achieve Ca2+homeostasis. Calcium ions are a criticalsecond messenger, intrinsic to intracellularsignal 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 induceapoptosis.
Ca2+-boundcalmodulin (CaM) interacts with Cav1.3 to induce calcium-dependent inactivation (CDI). Recently, it has been shown thatRNA 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.
Cav1.3 channels are widely expressed in humans.[15] Notably, their expression predominates in cochlea inner hair cells (IHCs). Cav1.3 have been shown throughpatch clamp experiments to be essential for normal IHC development andsynaptic transmission.[16] Therefore, Cav1.3 are required for proper hearing.[17]
Cav1.3 are densely expressed inchromaffin 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]
Parkinson's disease is the second most commonneurodegenerative disease, in which the death of dopamine-producing cells in thesubstantia nigra of themidbrain leads to impaired motor function, perhaps best characterised bytremor. 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 transients, which appears to make the dopaminergicsubstantia nigra neurones vulnerable tostressors 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 IIIArchived 2019-04-07 at theWayback Machine) testing this hypothesis in patients with early Parkinsons's failed to show efficacy in slowing the progression of Parkinson's.[20]
Inhibition of Cav1.3 can be achieved using calcium channel blockers, such asdihydropyridines (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.[21] 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.[22] However, its selectivity and potency could not be confirmed in two independent studies from two other groups.[23] One of them even reported gating changes induced by this drug., which indicate channel activating rather than blocking effects.[24]
Recent evidence fromimmunostaining experiments shows thatCACNA1D is highly expressed in prostate cancers compared with benign prostate tissues. Blocking L-type channels orknocking down gene expression ofCACNA1D 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 ofCACNA1D gene overexpression in prostate cancer cell growth.
^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.PMID30625283.S2CID58619079.
^Parkinson Study Group (November 2013). "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.doi:10.1002/mds.25639.PMID24123224.S2CID9594193.
^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.PMID24054868.
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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.PMID1324226.
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.PMID1849233.S2CID4370532.
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.PMID7557998.
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.PMID11160515.S2CID147295966.
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.PMID16973824.S2CID863259.
Overview of all the structural information available in thePDB forUniProt:Q01668 (Voltage-dependent L-type calcium channel subunit alpha-1D) at thePDBe-KB.
