Cav3.3
Description: calcium channel, voltage-dependent, T type, alpha 1I subunit Gene: Cacna1i Alias: cacna1i, cav3.3, ca3.3, Ca(v)3.3
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.
In humans, cacna1i, the gene which encodes Cav3.3, is composed of 37 exons located on chromosome 22 at position 13. (22q13.1).
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 |
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]
Isoforms
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]
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
Methodology for AlphaFold size prediction and disclaimer are available here
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]
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)
Animal | CH | |
CellType | CHO | |
Age | 0 Days | |
Temperature | 0.0°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)) |
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:
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]
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:
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]
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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Contributors: Rajnish Ranjan, Michael Schartner
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