T-type calcium channel
T-type calcium channels are
The distinct structures of T-type calcium channels are what allow them to conduct in these manners, consisting of a primary α1 subunit. The α1 subunit of T-type channels is the primary subunit that forms the pore of the channel, and allows for entry of calcium.
T-type calcium channels function to control the pace-making activity of the SA Node within the heart and relay rapid action potentials within the thalamus. These channels allow for continuous rhythmic bursts that control the SA Node of the heart.[3]
Pharmacological evidence of T-type calcium channels suggest that they play a role in several forms of
Further research is continuously occurring to better understand these distinct channels, as well as to create drugs to selectively target these channels.Chr. 17 q22 | |||||||
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Function
Like any other channel in a cell membrane, the primary function of the T-type voltage gated calcium channel is to allow passage of ions, in this case calcium, through the membrane when the channel is activated. When membrane depolarization occurs in a cell membrane where these channels are embedded, they open and allow calcium to enter the cell, which leads to several different cellular events depending on where in the body the cell is found. As a member of the Cav3 subfamily of voltage-gated calcium channels, the function of the T-type channel is important for the repetitive firing of action potentials in cells with rhythmic firing patterns such as cardiac muscle cells and neurons in the thalamus of the brain.
Heart
This is important in the aforementioned depolarization events in the pace-making activity of the sinoatrial (SA) Node in the heart and in the neuron relays of the thalamus so that quick transmission of action potentials can occur. This is very important for the heart when stimulated by the sympathetic nervous system that causes the heart rate to increase, in that not only does the T-type calcium channel provide an extra depolarization punch in addition to the voltage gated sodium channels to cause a stronger depolarization, but it also helps provide a quicker depolarization of the cardiac cells.[1][3]
Fast-acting
Another important facet of the T-type voltage gated calcium channel is its fast voltage-dependent inactivation compared to that of other calcium channels. Therefore, while they help provide stronger and quicker depolarization of cardiac muscle cells and thalamus nerve cells, T-type channels also allow for more frequent depolarization events. This is very important in the heart in the simple fact that the heart is better apt to increase its rate of firing when stimulated by the sympathetic nervous system innervating its tissues. Although all of these functions of the T-type voltage gated calcium channel are important, quite possibly the most important of its functions is its ability to generate potentials that allow for rhythmic bursts of action potentials in cardiac cells of the sinoatrial node of the heart and in the thalamus of the brain.[1] Because the T-type channels are voltage dependent, hyperpolarization of the cell past its inactivation voltage will close the channels throughout the SA node, and allow for another depolarizing event to occur. The voltage dependency of the T-type channel contributes to the rhythmic beating of the heart.[3]
Structure
α1 Subunit
The α1 subunit of T-type calcium channels is similar in structure to the α subunits of
Auxiliary subunits
The β, α2δ, and γ subunits are auxiliary subunits that affect channel properties in some calcium channels. The α2δ subunit is a dimer with an extracellular α2 portion linked to a transmembrane δ portion. The β subunit is an intracellular membrane protein. The α2δ and β subunits have an effect on the conductance and kinetics of the channel.[8] The γ subunit is a membrane protein that has an effect on the voltage sensitivity of the channel.[8] Current evidence shows that isolated T-type α1 subunits have similar behavior to natural T-type channels, suggesting that the β, α2δ, and γ subunits are absent from T-type calcium channels and the channels are made up of only an α1 subunit.[3]
Variation
There are three known types of T-type calcium channels, each associated with a specific α1 subunit.
Designation | α1 Subunit | Gene |
---|---|---|
Cav3.1 | α1G | (CACNA1G) |
Cav3.2 |
α1H | (CACNA1H) |
Cav3.3 | α1I | (CACNA1I) |
Pathology
When these channels are not functioning correctly, or are absent from their usual domains, several issues can result.
Cancer
T-type Calcium channels are expressed in different human cancers such as breast, colon, prostate,
Epilepsy
The major disease that involves the T-type calcium channel is
Pain
The Cav3.2 isoform of T-type calcium channels has been found to involve in pain in animal models with acute pain[10] and chronic pain: neuropathic pain[4][11] (PDN), inflammatory pain[12] and visceral pain.[13]
Parkinson's disease
Increased neuronal bursting occurs throughout the central motor system in both human forms and animals models of Parkinson's disease.[14] T-type calcium channels are highly expressed in basal ganglia structures as well as neurons in the motor areas of the thalamus and are thought to contribute to normal and pathological bursting by means of low-threshold spiking.[15] Basal ganglia recipient neurons in the thalamus are particularly interesting because they are directly inhibited by the basal ganglia output.[16] Consistent with the standard rate model of the basal ganglia, the increased firing in basal ganglia output structures observed in Parkinson's disease would exaggerate the inhibitory tone in thalamocortical neurons. This may provide the necessary hyperpolarization to de-inactivate T-type calcium channels, which can result in rebound spiking. In normal behavior, bursting likely plays a role in increasing the likelihood of synaptic transmission, initiating state changes between rest and movement, and might signal neural plasticity due to the intracellular cascades brought on by the rapid influx of calcium.[17] While these roles are not mutually exclusive, most attractive is the hypothesis that persistent bursting promotes a motor state resistant to change, potentially explaining the akinetic symptoms of Parkinson's disease.[18]
As a drug target
Calcium channel blockers (CCB) such as mibefradil can also block L-type calcium channels, other enzymes, as well as other channels.[4] Consequently, research is still being conducted to design highly selective drugs that can target T-type calcium channels alone.[4]
Cancer
Furthermore, since T-type calcium channels are involved in proliferation, survival and cell cycle progression of these cells, they are potential targets for anticancer therapy.
Painful Diabetic Neuropathy (PDN)
In addition, drugs used for treating PDN are associated with serious side effects and target specifically the CaV3.2 isoform (responsible for development of neuropathic pain in PDN) could reduce side effects.[6] As a result, research to improve or design new drugs is currently on-going.[6]
Parkinson's disease
T-type calcium channels represent an alternative approach to Parkinson's disease treatment as their primary influence is not concerning the central dopaminergic system. For example, they offer great potential in reducing side effects of dopamine replacement therapy, such as levodopa-induced dyskinesia. The co-administration of T-type calcium channel blockers with standard Parkinson's disease medications is most popular in Japan, and several clinical studies have shown significant efficacy.[7] However, most of these drugs are experimental and operate in a non-specific manner, potentially influencing sodium channel kinetics as well as dopamine synthesis. Novel T-type calcium channel inhibitors have recently been discovered which more selectively target the CaV3.3 channel sub-type expressed in central motor neurons, showing robust modulation in a rodent and primate models of Parkinson's disease.[15][19]
References
- ^ PMID 21746798.
- ^ PMID 21776294.
- ^ PMID 12506128.
- ^ S2CID 18238236.
- ^ PMID 16787249.
- ^ S2CID 15152953.
- ^ PMID 21180621.
- ^ ISBN 9780878936090.
- PMID 30734897.
- S2CID 21984943.
- S2CID 23847088.
- S2CID 5241999.
- PMID 21690417.
- PMID 22805066.
- ^ PMID 26538609.
- S2CID 8112392.
- PMID 24273509.
- PMID 22325204.
- PMID 22368764.