Channelpedia

Cav3.1

Description: calcium channel, voltage-dependent, T type, alpha 1G subunit
Gene: Cacna1g
Alias: cacna1g, cav3.1, ca3.1, Ca(v)3.1

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Introduction

Cav3.1, encoded by the gene cacna1g, is a calcium channel, voltage-dependent, T type, alpha 1G subunit. It is highly expressed in the brain and heart, where it is responsible for long term potentiation and pacemaking, respectively. Mutations of the channel are the cause of developmental disorders and cardiopathies.

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Gene

In humans, cacna1g, the gene which encodes Cav3.1, is composed of 38 exons located on chromosome 17 at position 21. (17q21.33). [2427]

Species NCBI gene ID Chromosome Position
Human 8913 17 66759
Mouse 12291 11 66009
Rat 29717 10 67962
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Transcript

Like most Cav channels, Cacna1g is subject to alternative splicing.

Some important exons, often involved in alternative splicing are [2481]:

  • Exon 25: alternative splicing of the exon gives rise to either a1G-a or a1G-b. a1g-b alternates 59-splice donor site of exon 25 combined with the acceptor site on exon 27
  • Exon 26: also known as insertion C which encodes for a section of the III-IV loop. It is generally only present alongside a1g-b
  • Exon 14: also known as insertion e which encodes for a section of the II-III loop .
  • Exon 34: also known as insertion f which encodes for a section of the COOH-terminal region.
  • Exon 35: also known as insertion d which encodes for another section of the COOH-terminal region
Species NCBI accession Length (nt)
Human NM_018896.5 8602
Mouse NM_009783.3 8238
Rat NM_001308302.1 7759
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Protein Isoforms

The human Cav3.1 protein is composed of 2377 amino acid (aa) and has a molecular weight of 262 Kda.

The CACNA1D gene undergoes extensive alternative splicing, leading to channels with subtle differences. The two variants, α1G-a and α1G-b, encode distinct intracellular III-IV loops. α1G-a is most similar to the canonical rat Cav3.1, while α1G-b has a shorter III-IV linker due to a 21-bp deletion.
These isoforms differ in expression: the α1G-a isoform, alone or combined with insertion e, is found in neuronal tissues, whereas α1G-b, mostly associated with insertion c, is detected in the fetal kidney. Additionally, α1G-b lacks the normally conserved phosphorylation sites. [2481]

Species Uniprot ID Length (aa)
Human O43497 2377
Mouse Q5SUF7 2381
Rat O54898 2254

Isoforms

Transcript
Length (nt)
Protein
Length (aa)
Variant
Isoform
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Post-Translational Modifications

A number of consensus phosphorylation sites for PKA and PKC were identified in Cav3.1, particularly in the intracellular regions, indicating that Cav3.1 may be subject to phosphorylation by these enzymes. [2481]
Phosphorylation is further evidenced by the activity of Rho-associated kinase (ROCK) on the channel. Activation of ROCK eversibly inhibited the peak current amplitudes of rat Ca(v)3.1 and Ca(v)3.3 channels without affecting the voltage dependence of activation or inactivation [2482]

PTM
Position
Type
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Structure

Like most Cav channels, Cav3.1 is made up of a single protein composed of 4 homologous domains (DI-DIV). Each domain is made up of 6 transmembrane subunits (S1-S6) connected by extracellular loops. S1-4 form the voltage sensing domain (VSD) whereas the S5-S6 act as the selectivity filter and forms the pore module (PM). The S4 subunit of each domain contains a series of positively charged residues. [2483]

The structure of a Cav3.1 isoform was resolved via electron-microscopy, to a resolution of 3.3 angstrom. This splice variant of rat Cav3.1 has a deletion within the I–II linker, designated Cav3.1-Δ8b, and was shown to increase surface expression. Despite its differences with the canonical protein, Cryo-EM of Cav3.1-Δ8b allows for a detailed insight into the specific structural features of the protein. [2483]

The structural features of Cav3.1 are [2483]:

  • Selectivity Filter (EEDD Motif): Cav3.1 has a unique selectivity filter composed of two Glutamate (Glu) and two Aspartate (Asp) residues, arranged as EEDD. This contrasts with the EEEE motif found in Cav1 and Cav2 channels, contributing to its distinctive calcium ion selectivity.
  • Disulfide Bond: A unique disulfide bond between Cys104 and Cys889 is present in Cav3.1, stabilizing the interaction between the voltage-sensing domain (VSD) I and the pore domain. This bond is specific to T-type channels like Cav3.1 and is involved in redox modulation.
  • Incompatibility with Auxiliary Subunits: Cav3.1 lacks the structural elements needed for binding with auxiliary subunits like α2δ, which are present in high-voltage-activated (HVA) channels. Specific extracellular loops (ECLI and ECLIII) in Cav3.1 would physically clash with these subunits, preventing their association.
  • Pore Domain Structure: The S5 and S6 helices form a pore domain that is characterized by a smaller constriction site compared to L-type channels. This structure is crucial for the specific ion conductance properties of Cav3.1.

These features collectively distinguish Cav3.1 from other voltage-gated calcium channels and contribute to its specific physiological functions.

Cav3.1 predicted AlphaFold size

Species Area (Å2) Reference
Human 9549.43 source
Mouse 10362.41 source
Rat 9226.06 source

Methodology for AlphaFold size prediction and disclaimer are available here

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Kinetics

Cav3.1 channels generate significant calcium currents by allowing entry of calcium into the cell in response to action potentials. [2484]

CaV3.1, CaV3.2, and CaV3.3 are characterized by their activation at low membrane potentials, close to the resting membrane potential, and transient single-channel conductance and are thus designated as the low-voltage-activated (LVA) or T-type channels. This is in contrast to Cav1 and Cav2, which are high-voltage-activated and conduct larger, long-lasting conductance. [2485] [2483]

The low voltage threshold for activation of T-type channels drives their opening in response to relatively small positive changes in membrane potential. Further, an overlap in the membrane potentials at which T-type channels open, close, and inactivate gives them a particular property known as a “window current” whereby a basal inward flux of calcium ions can occur near the resting potential [2484]

Cav3.1 also has its own particular gating properties [2484] [2486]:

  • Activation and Inactivation Kinetics: Cav3.1 channels have the fastest activation and inactivation kinetics among the T-type channels .
  • Voltage Dependence: Cav3.1 channels open and close at similar membrane potentials as Cav3.2 channels, but at more hyperpolarized potentials compared to Cav3.3.
  • Deactivation Kinetics: Cav3.1 channels deactivate (close) faster than Cav3.2 channels but slower than Cav3.3 channels.
  • Recovery from Inactivation: Cav3.1 channels recover from inactivation more quickly than Cav3.2 and Cav3.3 channels.
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Biophysics

Single channel unitary conductance

The single channel unitary conductance of Cav3.1 was at around 7 pS. [2481]

Model

Model Cav3.1 (ID=41)      

AnimalCH
CellType CHO
Age 0 Days
Temperature0.0°C
Reversal 30.0 mV
Ion Ca +
Ligand ion
Reference [103] Achraf Traboulsie et. al; J. Physiol. (Lond.) 2007 Jan 1
mpower 1.0
m Inf 1 /(1+exp((v-(-42.921064))/-5.163208))
m Tau -0.855809 + (1.493527 * exp(-v/27.414182)) If v lt -10
m Tau 1.0 If v gteq -10
hpower 1.0
h Inf 1 /(1+exp((v-(-72.907420))/4.575763))
h Tau 9.987873 + (0.002883 * exp(-v/5.598574))

MOD - xml - channelML

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Expression and Distribution

Tissues & Cellular

Cav3.1 can be found in different locations of the body. However, it’s predominant highly expressed in the brain, particularly in the thalamus, cerebellum (Purkinje neurons ), substantia nigra, and frontal and occipital lobes [2481] [2487]

Cav3.1 is also present at significant levels in the heart, including the sinoatrial node (SAN) and atrioventricular node (AVN), as well as in muscle sarcoma, the colon, lungs, breast, kidney, and reproductive organs such as the ovaries, placenta, testes, and prostate. [2399] [2422] [2481]

Developmental

Cav3.1 expression if thought tp be developmentally regulated. Though the channels expression is comparable in adult and fetal brains, it is more abundant in fetal peripheral tissues like the heart, kidneys, and lungs. This expression corroborates with fetal heart electrophysiological data, as T-type currents are preferentially recorded in embryonic heart cells. [2481]

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CNS Sub-cellular Distribution

There is little research on the suc-cellular location of Cav3.1 and location is likely dependent on the type of cell where the channel is present.
In retina nerve cells, Cav3.1 is localized to the somatodendritic compartment and proximal axon [2488]

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Function

Cav3.1’s role is to allow the entry of Ca2+ into the cell in a voltage dependent manner. Depending on its expressed location, the channel fulfills a number of function

Neuronal signalling

Cav3.1 is responsible for postsynaptic calcium signaling and long term potentiation. Among the T-type channels, CaV3.1 (α1G) channels produce larger, transient calcium currents that are essential for initiating action potentials. [2486] [2415]

Depending on which nerve cells and brain region they are present, the channels can have further functions. In neurons of the hypothalamic paraventricular nucleus, Cav3.1 is the major subtype that mediates T-type calcium channel-dependent low-threshold spikes (LTSs) [2489] In the thalamocortical relay neurons, CaV3.1 channels contribute significantly to burst firing in neurons and mediate low-threshold spikes essential for certain types of rhythmic activity, such as those observed in sleep and epilepsy. [2486]. KO Cav3.1 mice display no burst firing activity, were less prone to developing tonic seizures but did display some issues with motor performance and cerebellar learning [2487]

Sleep

Impaired Cav3.1 channels were shown to decrease sleep duration [2490] KO mice lacking the T-channel Cav3.1 subunit demonstrated that the activation of T-channels during wake-like states is a major determinant for single and multiple spike occurrence during tonic firing and for the robustness of the thalamocortical transfer of sensory inputs during sleep [2491]

Pacemaking

In the heart, Cav3.1 contributed to heart rate genesis by ensuring rep [2492] Disruption of channel abolishes the T-type calcium current in the SAN and the atrioventricular node. Inactivation of Cav3.1 lead to a significant slowing of in vivo heart rate, prolonged the SAN recovery time, and slowed pacemaker activity of individual SAN cells through a reduction of the slope of the diastolic depolarization [530]

Pain

Cav3.1 is not responsible for pain signalling as the channel is not expressed in the sensory ganglia and KO models reveled normal peripheral pain detection [2485]

Channelopathies

Given the importance of Cav3.1’s role through the body, mutations to coding gene or disruption to the protein are responsible for a number of pathologies

Developmental disorders

Given its important and predominant expression in the brain, aberrant Cav3.1 function leads to a number of cognitive impairment. These include [2487]:

  • Late-onset cerebellar ataxia ADCA/SCA42: Hereditary cerebellar ataxias are rare neurodegenerative disorders, characterized by a cerebellar syndromewith or without other neurological symptomsCACNA1G was linked to an autosomal dominant cerebellar ataxia (ADCA)
  • Childhood cerebellar atrophy: is a devastating infantile neurodevelopmental disorder, with severe motor and cognitive impairments, cerebellar atrophy, and variable features including facial dysmorphism, digital anomalies, microcephaly, hirsutism, and epilepsy.
  • Autism spectrum disorder: CACNA1G was identified as a candidate gene for autism spectrum disorder (ASD)
  • Epilepsy: Idiopathic generalized epilepsies (IGEs), Juvenile myoclonic epilepsy, severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE) [2493]
  • Parkinsons: Cav3.1 is the predominant form of T‐type channels in the dopaminergic neurons of the Substantia nigra pars compacta. SN is thought to play an emerging role in Parkinsons disorder. Cav3.1 TTCCs stabilize SN DA pacemaker frequency and its precision in an age‐dependent manner and therefore may have a hand in the development of parkinson [2494]

Cardiopathies

Cav3.1 is cruchal for the proper function of pacemaker cells in the sinoatrial node of the heart. These channels help regulate the heart's rhythm by contributing to the diastolic. Cav3.1 is a pathophysiological target for [2495]: Sinus Node Dysfunction (SND): Mutations in Cav3.1 channels are linked to sinus node dysfunction, a condition where the heart's natural pacemaker fails to function properly. This can lead to irregular heart rhythms (arrhythmias) or bradycardia (slow heart rate). Heart Block: Cav3.1 dysfunction can also contribute to atrioventricular (AV) block, where the electrical signals between the heart's chambers are delayed or blocked, potentially leading to severe arrhythmias [2495]

Cancer

Aberrant expression of cacna1g is common in a broad range of cancers. Cav3.1 is the top 1% of overexpressed genes in synovial sarcoma and prostate carcinoma but it is also highly expressed in other tumors such as colorectal, uterine, prostate, and breast cancer. Depending on the type, cacna1g can also be under-expressed in breast cancer [2422] [2440]

The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation is a distinct phenotype in cancer, particularly colorectal cancer. A high volume of evidence has shown that high methylation of Cacna1g promoter is an epigenetic marker for tumours.[2496] [2497] [2498] [2499] [2500] [2501]

Neonatal methylation markers on Cacna1g were also significantly associated with birth weight. [2502]

Endocrinopathies

Mutation in CACNA1D were found to cause aldosterone producing adenoma (APA) and familial hyperaldosteronism (FH)

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Interaction

Interestingly, Cav3.1 channels of function in the absence of auxiliary subunits as they lack the proper binding sites for proper interaction (see)Structure [2483] Indeed similarly, the G protein binding sites have not been identified nor Ca2+ and calmodulin binding domains involved in calcium dependent inactivation [2481]

Cav3.1 is sensitive to ions, particularly Zn2+. ZN2+ inhibition is associated with a shift to more negative membrane potentials of both Cav3.1 steady-state inactivation and steady-state activation currents. There are also changes in kinetics, especially a significant slowing of the inactivation kinetics. Application of Zn21 results significant reduction in current.[103]

Another notable inhibitor of T-type channels is Mibefradil. [2503]

CACHD1 is a protein highly expressed in the male mammalian CNS with similar distribution patterns as Cav3. subunits. CACHD1 was shown to increase cell-surface localization of CaV3.1, and caused a significant increase in peak current density and corresponding increases in maximal conductance, resulting in increased open probability of the channel and neuronal excitability. [2504]

Estrogen increases the expression of the Cav3.1 in certain brain regions, notablyin the hypothalamus and pituitary. The hormone also enhances the activity of these channels in neurons, leading to increased calcium currents and more burst firing. These modulations suggest that estrogen boosts the function of T-type calcium channels, which in turn enhances neuron firing and neurotransmitter release in the brain. [2505]

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References

103

Traboulsie A et al. Subunit-specific modulation of T-type calcium channels by zinc.
J. Physiol. (Lond.), 2007 Jan 1 , 578 (159-71).

104

Hansen JP et al. Calcium channel gamma6 subunits are unique modulators of low voltage-activated (Cav3.1) calcium current.
J. Mol. Cell. Cardiol., 2004 Dec , 37 (1147-58).

105

Niwa N et al. Cav3.2 subunit underlies the functional T-type Ca2+ channel in murine hearts during the embryonic period.
Am. J. Physiol. Heart Circ. Physiol., 2004 Jun , 286 (H2257-63).

106

Lacinova L et al. Modulation of gating currents of the Ca(v)3.1 calcium channel by alpha 2 delta 2 and gamma 5 subunits.
Arch. Biochem. Biophys., 2004 May 15 , 425 (207-13).

477

Catterall WA Structure and regulation of voltage-gated Ca2+ channels.
Annu. Rev. Cell Dev. Biol., 2000 , 16 (521-55).

528

Perez-Reyes E Molecular physiology of low-voltage-activated t-type calcium channels.
Physiol. Rev., 2003 Jan , 83 (117-61).

529

Hagiwara N et al. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells.
J. Physiol. (Lond.), 1988 Jan , 395 (233-53).

531

Huguenard JR Low-threshold calcium currents in central nervous system neurons.
Annu. Rev. Physiol., 1996 , 58 (329-48).

532

Anderson MP et al. Thalamic Cav3.1 T-type Ca2+ channel plays a crucial role in stabilizing sleep.
Proc. Natl. Acad. Sci. U.S.A., 2005 Feb 1 , 102 (1743-8).

534

Arnoult C et al. Activation of mouse sperm T-type Ca2+ channels by adhesion to the egg zona pellucida.
Proc. Natl. Acad. Sci. U.S.A., 1996 Nov 12 , 93 (13004-9).

2399

Marionneau C et al. Specific pattern of ionic channel gene expression associated with pacemaker activity in the mouse heart.
J. Physiol. (Lond.), 2005 Jan 1 , 562 (223-34).

2415

Kessi M et al. Calcium channelopathies and intellectual disability: a systematic review.
Orphanet J Rare Dis, 2021May13, 16 (219).

2440

Phan NN et al. Voltage-gated calcium channels: Novel targets for cancer therapy.
Oncol Lett, 2017Aug, 14 (2059-2074).

2481

Monteil A et al. Molecular and functional properties of the human alpha(1G) subunit that forms T-type calcium channels.
J. Biol. Chem., 2000 Mar 3 , 275 (6090-100).

2482

Iftinca M et al. Regulation of T-type calcium channels by Rho-associated kinase.
Nat. Neurosci., 2007 Jul , 10 (854-60).

2483

Zhao Y et al. Cryo-EM structures of apo and antagonist-bound human Cav3.1.
Nature, 2019Dec, 576 (492-497).

2484

Cain SM et al. Contributions of T-type calcium channel isoforms to neuronal firing.
Channels (Austin), 2010 Nov-Dec , 4 (475-82).

2487

Lory P et al. Neuronal Cav3 channelopathies: recent progress and perspectives.
Pflugers Arch, 2020Jul, 472 (831-844).

2489

Zhang C et al. 17Beta-estradiol regulation of T-type calcium channels in gonadotropin-releasing hormone neurons.
J. Neurosci., 2009 Aug 26 , 29 (10552-62).

2490

Tatsuki F et al. Involvement of Ca(2+)-Dependent Hyperpolarization in Sleep Duration in Mammals.
Neuron, 2016Apr06, 90 (70-85).

2491

Deleuze C et al. T-type calcium channels consolidate tonic action potential output of thalamic neurons to neocortex.
J. Neurosci., 2012 Aug 29 , 32 (12228-36).

2498

Qu Y et al. Gene methylation in gastric cancer.
Clin Chim Acta, 2013Sep23, 424 (53-65).

2504

Cottrell GS et al. CACHD1 is an α2δ-Like Protein That Modulates CaV3 Voltage-Gated Calcium Channel Activity.
J Neurosci, 2018Oct24, 38 (9186-9201).

2505

Qiu J et al. Estrogen upregulates T-type calcium channels in the hypothalamus and pituitary.
J. Neurosci., 2006 Oct 25 , 26 (11072-82).

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Credits

Contributors: Rajnish Ranjan, Michael Schartner

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/85/ , accessed on 2024 Dec 21