Channelpedia

Cav3.3

Description: calcium channel, voltage-dependent, T type, alpha 1I subunit
Gene: Cacna1i
Alias: cacna1i, cav3.3, ca3.3, Ca(v)3.3

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Introduction

Cav3.3, encoded by the gene cacna1i, is a calcium channel, voltage-dependent, T type, alpha 1I subunit. It is highly expressed in the brain, where it is responsible for burst firing. Mutations of the channel are the cause of developmental disorders, particularly, schizophrenia.

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Gene

In humans, cacna1i, the gene which encodes Cav3.3, is composed of 37 exons located on chromosome 22 at position 13. (22q13.1).

Species NCBI gene ID Chromosome Position
Human 8911 22 118982
Mouse 239556 15 111054
Rat 56827 7 111422
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Transcript

As with most Cav channels, cacna1i is subject to alternative splicing.

Some important exons, often involved in alternative splicing are [2525]:

  • Exon 9: which adds 35 amino acids.
  • Exon 33: Splicing within exon 33 leads to a 13 amino acid deletion (Δ33).
Species NCBI accession Length (nt)
Human NM_021096.4 10002
Mouse NM_001044308.2 9833
Rat NM_020084.3 6709
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Protein Isoforms

The human Cav3.3 protein is composed of 2223 amino acid (aa) and has a molecular weight of 245 Kda.

The CACNA1i gene undergoes extensive alternative splicing, leading to channels with subtle differences.

Cav3.3 isoforms lacking exon 9 (Δ9) recover faster from inactivation and show a steeper voltage dependence of inactivation compared to channels with exon 9. [2525]

Alternative splicing of exon 33, more specifically the region between exons 33 & 34, yields three key splice variants: Cav3.3Δ33, Cav3.3a, Cav3.3b, and Cav3.3c. These isoforms have variations in their carboxy-termini, leading to altered channel kinetics.

  • Cav3.3a lacks the sequences found in b and c, and Exhibits the fastest activation and inactivation kinetics.
  • Cav3.3b includes 40 extra nucleotides and has slower kinetics compared to Cav3.3a
  • Cav3.3c includes 121 extra nucleotides and displays the slowest kinetics.
  • Cav3.3Δ33 exhibits even slower activation and inactivation compared to their full-length counterparts [2526]
Species Uniprot ID Length (aa)
Human Q9P0X4 2223
Mouse E9Q7P2 2199
Rat Q9Z0Y8 2201

Isoforms

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

Little research has been conducted on Cav3.3 post translational modifications.

However, there is some evidence that phosphorylation regulates Cav3.3, particularly its activity-dependent Ca2+ inhibition behaviour [2487]

Some N-glycosylation sites have also been identified during structural studies [2527]

PTM
Position
Type
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Structure

Like most Cav channels, Cav3.3 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 Cav3.3 isoform was resolved via electron-microscopy, to a resolution of 3.3 Å, allowing for a detailed insight into the specific structural features of the protein. [2527]:

  • Extended S6 Helix in Domain III (S6III):
    • A key structural feature of Cav3.3 is a long, bended S6 helix from domain III, extending into the cytosol. This extension is absent in other high-voltage-activated (HVA) calcium channels like CaV1 and CaV2.
    • S6III helix has a positively charged cytoplasmic region (S6Cyto), which contributes to the channel's low-voltage activation properties. Mutations to this region shift the channel's voltage dependence, rendering iit less sensitive to low voltages.
  • Unique Phospholipid Interactions:
    • In the CaV3.3 channel, phospholipids penetrate the central cavity from domain interfaces, enhancing stability. Unlike CaV3.1, where phospholipids enter through the domain II–III fenestration, in CaV3.3, they enter from the domain III–IV interface, highlighting a structural difference that affects how these channels interact with their surrounding lipids​
  • Selectivity Filter and Ion Conduction:
    • The selectivity filter of CaV3.3, like other calcium channels, is formed by the EEDD (glutamate, aspartate) motif, which controls calcium ion permeation.
  • Gating Mechanism:
    • CaV3.3 features slower kinetics, both in activation and inactivation, compared to other T-type channels such as CaV3.1 and CaV3.2, making it better suited for controlling sustained firing in neurons.

Cav3.3 predicted AlphaFold size

Species Area (Å2) Reference
Human 9798.13 source
Mouse 9959.28 source
Rat 10633.19 source

Methodology for AlphaFold size prediction and disclaimer are available here

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Kinetics

Cav3.3 T-channel current displayed slowly activating and inactivating kinetics. [112]

Cav3.3 by contrast is easily distinguishable by its slower activation and inactivation kinetics. [2528]

In exogenous systems the CaV3.1 and CaV3.2 T-types generally open and close at approximately similar membrane potentials, while CaV3.3 channels open and close at about +10 mV more depolarized potentials.9 Similarly, CaV3.1 and CaV3.2 channels inactivate (as determined at steady-state) around 5 mV more hyperpolarized than CaV3.3 channels and, therefore, require more hyperpolarized potentials to become available for subsequent opening via de-inactivation. CaV3.1 channels display the fastest activation and inactivation kinetics, marginally faster than CaV3.2, and both of which are significantly faster than for CaV3.3 channels.9,10 Therefore, CaV3.1 and CaV3.2 channels open fastest in response to depolarization when compared to CaV3.3, but are also quickest to inactivate during depolarization. Conversely, CaV3.3 channels display the fastest deactivation kinetics, far faster than CaV3.1, which is marginally faster than CaV3.2 and, therefore, upon repolarization CaV3.3 channels are the quickest to close when the membrane potential begins to repolarize. With respect to the rate at which the T-subtypes recover from inactivation, CaV3.1 channels display the fastest rate of recovery, followed by CaV3.3 and with CaV3.2 being the slowest. Experiments utilizing mock action potentials demonstrated that the CaV3.1 and CaV3.2 channels display similar amplitude currents in response to a single action potential, while due to the slower activation kinetics of CaV3.3 channels the resulting currents are significantly smaller.[2484]

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Biophysics

Single channel unitary conductance

The single channel unitary conductance of Cav3.3 has not been measured as of yet.

Model

Model Cav3.3 (ID=42)      

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- -45.454426)/-5.073015))
m Tau 3.394938 +( 54.187616 / (1 + exp((v - -40.040397)/4.110392)))
hpower 1.0
h Inf 1 /(1+exp((v-(-74.031965))/8.416382))
h Tau 109.701136 + (0.003816 * exp(-v/4.781719))

MOD - xml - channelML

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Expression and Distribution

Cav3.1 can be found in different locations of the body. However, it’s predominant highly expressed in the brain, particularly in the thalamus, particularly the nucleus reticularis thalami (nRt) [2529] [2415] [2530]

It has also been identified in other regions, such as:

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CNS Sub-cellular Distribution

Subcellular distribution of Cav3.3 depends on the localisation of the channel. In purkinje cells, the channel was predominantly identified in the dendrites and soma [2533]

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Function

Given its kinetics properties, Cav3.3 plays a role in sustained firing in neurons where it is expressed. In its predominant expression location, the reticular thalamic neurons (nRt), CaV3.3 channels are essential for generating rhythmic bursting which is critical for producing sleep spindles—a key feature of non-REM sleep. CaV3.3-mediated bursts, along with GluN2B-containing NMDA receptors, strengthen connections in thalamoreticular synapses, showing that sleep enhances intrathalamic circuits​. Removing CaV3.3 channels in mice abolishes the low-frequency (4-10 Hz) oscillatory bursts required for sleep spindles, while regular tonic firing remains unaffected. This deletion also eliminates low-threshold calcium currents and spindles in the EEG, with further disruption seen when CaV3.2 channels are also removed, amplifying the negative effects on brain activity​. These channels also regulate sleep spindle variability, influencing their frequency and amplitude across different brain regions​. [2534] [2535] [2487] [2536]

CaV3.3 channels play a crucial role in mediating cerebral arterial constriction at lower intraluminal pressures [2532]

Channelopathies

Given the importance of Cav3.3’s roles, mutations to coding gene or disruption to the protein are responsible for a number of pathologies.

GWAS (genome-wide association studies) have identified genome-wide significant associations at loci including cacna1c and cacna1i for schizophrenia [2537] [2538] [2539] Schizophrenia is defined by waking phenomena, of which abnormal sleep is a common feature. Growing evidence points to the cause being a sleep spindle deficit. As previously discussed, Cav3.3 is largely present in these sleep spindles and is responsible for the regulation of their burst firing. [2530]

Cav3.3 mutation are associated with other neurodevelopmental disorders. Mutations in the channel gate region result in slowed channel kinetics, altered voltage sensitivity, and increased calcium influx, leading to neuron hyperexcitability. These changes likely cause calcium toxicity, contributing to the patients' cognitive impairments and seizures [2540]. Some pathologies include:

  • Impulsive personality traits [2541]
  • Autism spectrum disorder [2460]

CaV3.3 (cacna1i) is also notably under-expressed in both brain tumors and breast cancer [2440]. Additionally, certain mutations in cacna1i are linked to more aggressive breast cancer types, including invasive breast carcinoma stroma and ductal carcinoma in situ, suggesting that altered CaV3.3 calcium transport function may contribute to cancer progression and cellular dysregulation [2422]

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Interaction

So far no auxiliary subunits were shown to interact the activity of Cav3.3. however a number of other molecules and compounds have been demonstrated to modulate the channel:

  • Zinc: slows both the inactivation and deactivation kinetics of Cav3.3. However, the Cav3.3 is 100 fold less sensitive to Zinc in comparison to other T-type channels. [103]
  • Nickel, Niflumic acid, and mibefradil are well established blockers of Cav3.3 [2415]
  • N-arachidonoyl glycine (NAGly) is a reversible inhibitor of Cav3.3 [2542]
  • Phorbol-12-myristate-13-acetate (PMA) can enhance the current amplitude of cav3.3 without disruption the whole cell current [112]
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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).

113

Park JY et al. Multiple structural elements contribute to the slow kinetics of the Cav3.3 T-type channel.
J. Biol. Chem., 2004 May 21 , 279 (21707-13).

114

T-type Ca2+ channels encode prior neuronal activity as modulated recovery rates.
J. Physiol. (Lond.), 2006 Mar 15 , 571 (519-36).

115

Cataldi M et al. Zn(2+) slows down Ca(V)3.3 gating kinetics: implications for thalamocortical activity.
J. Neurophysiol., 2007 Oct , 98 (2274-84).

340

Randall AD et al. Contrasting biophysical and pharmacological properties of T-type and R-type calcium channels.
Neuropharmacology, 1997 Jul , 36 (879-93).

528

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

1237

Armstrong CM et al. Two distinct populations of calcium channels in a clonal line of pituitary cells.
Science, 1985 Jan 4 , 227 (65-7).

1238

Carbone E et al. A low voltage-activated, fully inactivating Ca channel in vertebrate sensory neurones.
Nature, 1984 Aug 9-15 , 310 (501-2).

1239

Perez-Reyes E et al. Molecular characterization of a neuronal low-voltage-activated T-type calcium channel.
Nature, 1998 Feb 26 , 391 (896-900).

1243

Kim D et al. Thalamic control of visceral nociception mediated by T-type Ca2+ channels.
Science, 2003 Oct 3 , 302 (117-9).

1244

Ikeda H et al. Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia.
Science, 2003 Feb 21 , 299 (1237-40).

1245

Shin JB et al. A T-type calcium channel required for normal function of a mammalian mechanoreceptor.
Nat. Neurosci., 2003 Jul , 6 (724-30).

1246

Kawai F et al. Enhancement by T-type Ca2+ currents of odor sensitivity in olfactory receptor cells.
J. Neurosci., 2001 May 15 , 21 (RC144).

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).

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).

2515

Wang R et al. The Cav3.2 T-type calcium channel regulates temporal coding in mouse mechanoreceptors.
J. Physiol. (Lond.), 2011 May 1 , 589 (2229-43).

2525

Murbartián J et al. Functional impact of alternative splicing of human T-type Cav3.3 calcium channels.
J. Neurophysiol., 2004 Dec , 92 (3399-407).

2527

He L et al. Structure, gating, and pharmacology of human CaV3.3 channel.
Nat Commun, 2022Apr19, 13 (2084).

2532

Harraz OF et al. CaV1.2/CaV3.x channels mediate divergent vasomotor responses in human cerebral arteries.
J. Gen. Physiol., 2015 May , 145 (405-18).

2534

Astori S et al. The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus.
Proc. Natl. Acad. Sci. U.S.A., 2011 Aug 16 , 108 (13823-8).

2535

Fernandez LM et al. Thalamic reticular control of local sleep in mouse sensory cortex.
Elife, 2018Dec25, 7 ().

2542

Barbara G et al. T-type calcium channel inhibition underlies the analgesic effects of the endogenous lipoamino acids.
J. Neurosci., 2009 Oct 21 , 29 (13106-14).

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Credits

Contributors: Rajnish Ranjan, Michael Schartner

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/87/ , accessed on 2024 Dec 21