Cav1.3

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

Structure and function
is_associated_with::Voltage-dependent calcium channels (VDCC) are selectively permeable to is_associated_with::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 is_associated_with::muscle contraction, is_associated_with::gene expression, and is_associated_with::secretion. Calcium-dependent processes can be halted by lowering intracellular calcium levels, which, for example, can be accomplished by is_associated_with::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 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 is_associated_with::dihydropyridines. The remaining β, α2δ and γ subunits have auxiliary functions.

The α1 subunit has four is_associated_with::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 is_associated_with::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 is_associated_with::neurotransmitter release in is_associated_with::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. Cav1.3 have a low affinity for DHP and activate at sub-threshold membrane potentials, making them ideal for a role in cardiac pacemaking.

Alternative Splicing
Post-transcriptional is_associated_with::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, 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.

Negative Feedback
Cav1.3 channels are regulated by is_associated_with::negative feedback to achieve Ca2+ is_associated_with::homeostasis. Calcium ions are a critical second messenger, intrinsic to intracellular is_associated_with::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 is_associated_with::apoptosis.

Ca2+-bound is_associated_with::calmodulin (CaM) interacts with Cav1.3 to induce calcium-dependent inactivation (CDI). Recently, it has been shown that is_associated_with::RNA editing of Cav1.3 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.

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

Chromaffin Cells
Cav1.3 are densely expressed in is_associated_with::chromaffin cells. The low-voltage activation and slow inactivation of these channels makes them ideal for controlling excitability in these cells. is_associated_with::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.

Neurodegeneration
is_associated_with::Parkinson's disease is the second most common neurodegenerative disease, in which the death of dopamine-producing cells in the is_associated_with::substantia nigra of the is_associated_with::midbrain leads to impaired motor function, perhaps best characterised by is_associated_with::tremor. Recent evidence suggests that L-type Cav1.3 Ca2+ channels contribute to the death of dopaminergic neurones in patients with Parkinson's disease. 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 is_associated_with::stressors that contribute to their death. Results suggest that inhibition of Cav1.3 is protective against the pathogenesis of Parkinson's.

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.

Prostate Cancer
Recent evidence from is_associated_with::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
Mutations in the S6 segment of CACNA1D are associated with is_associated_with::primary aldosteronism, which causes is_associated_with::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 is_associated_with::aldosterone production.