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).
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]
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]
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.
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]
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]
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 transients, 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 Archived 2019-04-07 at the Wayback 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 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. [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 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. [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 of CACNA1D gene overexpression in prostate cancer cell growth.
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. [26] [27] The number of validated APA mutations is constantly growing. [28] In rare cases, APA mutations have also been found as germline mutations in individuals with neurodevelopmental disorders of different severity, including autism spectrum disorder. [26] [28] [29]
Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are also frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, and to reduce chest pain caused by angina pectoris.
Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.
Calcium channel, voltage-dependent, L type, alpha 1C subunit is a protein that in humans is encoded by the CACNA1C gene. Cav1.2 is a subunit of L-type voltage-dependent calcium channel.
T-type calcium channels are low voltage activated calcium channels that become inactivated during cell membrane hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different physiological responses associated with it. Within cardiac muscle cell and smooth muscle cells voltage-gated calcium channel activation initiates contraction directly by allowing the cytosolic concentration to increase. Not only are T-type calcium channels known to be present within cardiac and smooth muscle, but they also are present in many neuronal cells within the central nervous system. Different experimental studies within the 1970s allowed for the distinction of T-type calcium channels from the already well-known L-type calcium channels. The new T-type channels were much different from the L-type calcium channels due to their ability to be activated by more negative membrane potentials, had small single channel conductance, and also were unresponsive to calcium antagonist drugs that were present. These distinct calcium channels are generally located within the brain, peripheral nervous system, heart, smooth muscle, bone, and endocrine system.
The R-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit forms the pore through which calcium enters the cell and determines most of the channel's properties. This α1 subunit is also known as the calcium channel, voltage-dependent, R type, alpha 1E subunit (CACNA1E) or Cav2.3 which in humans is encoded by the CACNA1E gene. They are strongly expressed in cortex, hippocampus, striatum, amygdala and interpeduncular nucleus.
The P-type calcium channel is a type of voltage-dependent calcium channel. Similar to many other high-voltage-gated calcium channels, the α1 subunit determines most of the channel's properties. The 'P' signifies cerebellar Purkinje cells, referring to the channel's initial site of discovery. P-type calcium channels play a similar role to the N-type calcium channel in neurotransmitter release at the presynaptic terminal and in neuronal integration in many neuronal types.
N-type calcium channels also called Cav2.2 channels are voltage gated calcium channels that are localized primarily on the nerve terminals and dendrites as well as neuroendocrine cells. The calcium N-channel consists of several subunits: the primary subunit α1B and the auxiliary subunits α2δ and β. The α1B subunit forms the pore through which the calcium enters and helps to determine most of the channel's properties. These channels play an important role in the neurotransmission during development. In the adult nervous system, N-type calcium channels are critically involved in the release of neurotransmitters, and in pain pathways. N-type calcium channels are the target of ziconotide, the drug prescribed to relieve intractable cancer pain. There are many known N-type calcium channel blockers that function to inhibit channel activity, although the most notable blockers are ω-conotoxins.
The L-type calcium channel is part of the high-voltage activated family of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. This channel has four isoforms: Cav1.1, Cav1.2, Cav1.3, and Cav1.4.
Cav2.1, also called the P/Q voltage-dependent calcium channel, is a calcium channel found mainly in the brain. Specifically, it is found on the presynaptic terminals of neurons in the brain and cerebellum. Cav2.1 plays an important role in controlling the release of neurotransmitters between neurons. It is composed of multiple subunits, including alpha-1, beta, alpha-2/delta, and gamma subunits. The alpha-1 subunit is the pore-forming subunit, meaning that the calcium ions flow through it. Different kinds of calcium channels have different isoforms (versions) of the alpha-1 subunit. Cav2.1 has the alpha-1A subunit, which is encoded by the CACNA1A gene. Mutations in CACNA1A have been associated with various neurologic disorders, including familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6.
Cav1.4 also known as the calcium channel, voltage-dependent, L type, alpha 1F subunit (CACNA1F), is a human gene.
Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is a protein which in humans is encoded by the CACNA1S gene. It is also known as CACNL1A3 and the dihydropyridine receptor.
Voltage-dependent L-type calcium channel subunit beta-2 is a protein that in humans is encoded by the CACNB2 gene.
Voltage-dependent L-type calcium channel subunit beta-4 is a protein that in humans is encoded by the CACNB4 gene.
Voltage-dependent L-type calcium channel subunit beta-1 is a protein that in humans is encoded by the CACNB1 gene.
Voltage-dependent L-type calcium channel subunit beta-3 is a protein that in humans is encoded by the CACNB3 gene.
Voltage-dependent calcium channel subunit alpha-2/delta-1 is a protein that in humans is encoded by the CACNA2D1 gene.
Calcium channel, voltage-dependent, T type, alpha 1H subunit, also known as CACNA1H, is a protein which in humans is encoded by the CACNA1H gene.
Voltage-dependent calcium channel gamma-1 subunit is a protein that in humans is encoded by the CACNG1 gene.
The voltage-dependent N-type calcium channel subunit alpha-1B is a protein that in humans is encoded by the CACNA1B gene. The α1B protein, together with β and α2δ subunits forms N-type calcium channel. It is a R-type calcium channel.
Diane Lipscombe is a British neuroscientist who is a professor of neuroscience and the Reliance Dhirubhai Ambani Director of Brown University’s Robert J. and Nancy D. Carney Institute for Brain Science. She served as the president of the Society for Neuroscience in 2019, the world’s largest organization for the study of the brain and nervous system.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.
