T-type calcium channel
   HOME

TheInfoList



OR:

T-type calcium channels are
low voltage In electrical engineering, low voltage is a relative term, the definition varying by context. Different definitions are used in electric power transmission and distribution, compared with electronics design. electrical safety codes define "low vo ...
activated
calcium channel A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, although there are also ligand-gated calcium channels. Comparison tables The following tables e ...
s that become inactivated during
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different
physiological Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
responses associated with it. Within
cardiac muscle cell Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
and
smooth muscle cell Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
s
voltage-gated calcium channel 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 permeabi ...
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 (transient opening calcium channels) from the already well-known
L-type calcium channels The L-type calcium channel (also known as the dihydropyridine channel, or DHP 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 c ...
(Long-Lasting 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 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 The sinoatrial node (also known as the sinuatrial node, SA node or sinus node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approximat ...
within the heart and relay rapid action potentials within the
thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
. These channels allow for continuous rhythmic bursts that control the SA Node of the heart. Pharmacological evidence of T-type calcium channels suggest that they play a role in several forms of
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
,
absence epilepsy Absence seizures are one of several kinds of generalized seizures. These seizures are sometimes referred to as petit mal seizures (from the French for "little illness", a term dated in the late 18th century). Absence seizures are characterized by ...
,
pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
, and
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
. Further research is continuously occurring to better understand these distinct channels, as well as to create drugs to selectively target these channels.


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. T-type calcium channels are activated in the same range as
voltage-gated Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins ...
sodium channels Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
, which is at about -55 mV. Because of this very negative value at which these channels are active, there is a large driving force for calcium going into the cell. The T-type channel is regulated by both
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
and other neurotransmitters, which inhibit T-type currents. Additionally, in certain cells
angiotensin Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrena ...
II enhances the activation of T-type channels.


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 The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of th ...
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.


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 The sinoatrial node (also known as the sinuatrial node, SA node or sinus node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approximat ...
of the heart and in the
thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
of the brain. 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.


Structure

Voltage-gated calcium channels 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 permeabili ...
are made up of several subunits. The α1 subunit is the primary subunit that forms the transmembrane pore of the channel. The α1 subunit also determines the type of calcium channel. The β, α2δ, and γ subunits, present in only some types of calcium channels, are auxiliary subunits that play secondary roles in the channel.


α1 Subunit

The α1 subunit of T-type calcium channels is similar in structure to the α subunits of K+(potassium ion) channels, Na+(sodium ion) channels, and other Ca2+(calcium ion) channels. The α1 subunit is composed of four domains (I-IV), with each domain containing 6 transmembrane segments (S1-S6). The hydrophobic loops between the S5 and S6 segments of each domain form the pore of the channel. The S4 segment contains a high quantity of positively charged residues and functions as the voltage sensor of the channel opening or closing based on the membrane potential. The exact method by which the S4 segment controls the opening and closing of the channel is currently unknown.


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. The γ subunit is a membrane protein that has an effect on the voltage sensitivity of the channel. 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.


Variation

There are three known types of T-type calcium channels, each associated with a specific α1 subunit.


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,
insulinoma An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin. It is a rare form of a neuroendocrine tumour. Most insulinomas are benign in that they grow exclusively at their origin within the pancreas, but a min ...
,
retinoblastoma Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and it is almost exclusively fo ...
,
leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
, ovarian, and
melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
, and they also play key roles in proliferation, survival, and the regulation of
cell cycle progression The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subse ...
in these forms of cancer . This was demonstrated through studies that showed that down regulating T-type channel isoforms, or just blocking the T-type calcium channels caused
cytostatic Cytostasis (cyto – cell; stasis – stoppage) is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division. Cytostasis is an important prerequisite for structured multic ...
effects in cancer cells such as
gliomas A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...
, breast, melanomas, and ovarian, esophageal, and colorectal cancers . Some of the most notorious forms of cancer tumors contain
cancer stem cells Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sampl ...
(CSC), which makes them particularly resistant to any cancer therapy . Furthermore, there is evidence that suggests that the presence of the CSC in human tumors may be associated with the expression of T-type calcium channels in the tumors.


Epilepsy

The major disease that involves the T-type calcium channel is
absence epilepsy Absence seizures are one of several kinds of generalized seizures. These seizures are sometimes referred to as petit mal seizures (from the French for "little illness", a term dated in the late 18th century). Absence seizures are characterized by ...
. This disease is caused by mutations of T-type calcium channel itself. Individuals with absence seizures have brief periods of behavioral arrest and unresponsiveness. Experiments on the Genetic Absence Epilepsy Rat of Strasbourg ( GAERS) suggested that absence epilepsy in the rat was linked to T-type channel protein expression. In fact, neurons isolated from the
reticular nucleus of the thalamus The thalamic reticular nucleus is part of the ventral thalamus that forms a capsule around the thalamus laterally. However, recent evidence from mice and fish question this statement and define it as a dorsal thalamic structure. It is separated fro ...
of the GAERS showed 55% greater T-type currents, and these currents were attributed to an increase in the Cav3.2 mRNA, according to Tally et al. suggesting that T-type protein expression was up regulated in the GAERS. Further experiments on the GAERS showed that, indeed, the expression of T-type calcium channels play a key role in seizures caused by absence epilepsy in the GAERS. Also, other evidence suggest that T-type calcium channel expression is not only up regulated in absence epilepsy, but also in other forms of epilepsy as well. The first-line treatments for
childhood absence epilepsy Childhood absence epilepsy (CAE), is one of the most frequent pediatric epilepsy syndromes. CAE is an idiopathic generalized epilepsy that occurs in otherwise normal children. The only seizure type at the time of diagnosis is the typical absence s ...
,
valproate Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...
and
ethosuximide Ethosuximide, sold under the brand name Zarontin among others, is a medication used to treat absence seizures. It may be used by itself or with other antiseizure medications such as valproic acid. Ethosuximide is taken by mouth. Ethosuximide ...
, are both blockers of T-type calcium channels; the second-line treatment,
lamotrigine Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut synd ...
, although not a T-type calcium channel blocker, does inhibit high-voltage activated calcium channels.


Pain

The Cav3.2 isoform of T-type calcium channels has been found to involve in
pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
in animal models with acute pain and chronic pain:
neuropathic pain Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous ...
(PDN), inflammatory pain and
visceral pain Visceral pain is pain that results from the activation of nociceptors of the thoracic, pelvic, or abdominal viscera (organs). Visceral structures are highly sensitive to distension (stretch), ischemia and inflammation, but relatively insensitive to ...
.


Parkinson's disease

Increased neuronal bursting occurs throughout the central motor system in both human forms and animals models of Parkinson's disease. T-type calcium channels are highly expressed in
basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...
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. Basal ganglia recipient neurons in the thalamus are particularly interesting because they are directly inhibited by the basal ganglia output. 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 Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...
, initiating state changes between rest and movement, and might signal
neural plasticity Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that differs from how it ...
due to the intracellular cascades brought on by the rapid influx of calcium. 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.


As a drug target

Calcium channel blocker 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 ...
s (CCB) such as
mibefradil Mibefradil (trade name Posicor) was a pharmaceutical drug used for the treatment of hypertension and chronic angina pectoris. It is a nonselective calcium channel blocker. It was voluntary pulled from the market ten months after FDA approval, cit ...
can also block L-type calcium channels, other enzymes, as well as other channels. Consequently, research is still being conducted to design highly selective drugs that can target T-type calcium channels alone.


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. Like mentioned above, blockage or down regulation of the T-type calcium channels causes
cytostasis Cytostasis (cyto – cell; stasis – stoppage) is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division. Cytostasis is an important prerequisite for structured multic ...
in tumors; but this blockage or down regulation of the T-channels may also induce cytotoxic effects. Consequently, it is not yet clear what the benefits or disadvantages of targeting T-type calcium channels in anticancer therapy are. On the other hand, a combined therapy involving administration of a T-type channel
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
followed by cytotoxic therapy is currently in its
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
phase.


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. As a result, research to improve or design new drugs is currently on-going.


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 Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% o ...
. For example, they offer great potential in reducing side effects of dopamine replacement therapy, such as
levodopa-induced dyskinesia Levodopa-induced dyskinesia (LID) is a form of dyskinesia associated with levodopa (l-DOPA), used to treat Parkinson's disease. It often involves hyperkinetic movements, including chorea, dystonia, and athetosis. In the context of Parkinson's dis ...
. 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. 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.


References

{{reflist, 33em Calcium channels