Cav1.3

3LV377612289ENSG00000157388ENSMUSG00000015968Q01668Q99246NM_000720NM_001128839NM_001128840NM_001083616NM_028981NM_001302637NP_000711NP_001122311NP_001122312NP_001077085NP_001289566NP_083257Calcium 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. Cav1.3 channels belong to the Cav1 family, which form L-type calcium currents and are sensitive to selective inhibition by dihydropyridines (DHP).2be6: 2.0 A crystal structure of the CaV1.2 IQ domain-Ca/CaM complex 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. Cav1.3 channels belong to the Cav1 family, which form L-type calcium currents and are sensitive to selective inhibition by dihydropyridines (DHP). 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. 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. Cav1.3 have a low affinity for DHP and activate at sub-threshold membrane potentials, making them ideal for a role in cardiac pacemaking. 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, 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. 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. 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. 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. Therefore, Cav1.3 are required for proper hearing.