T-type calcium channel

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T-type calcium channels are low voltage activated calcium channels that become inactivated during cell membrane hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different physiological responses associated with it. Within cardiac muscle cell and smooth muscle cells voltage-gated calcium channel 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 (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. [1] These distinct calcium channels are generally located within the brain, peripheral nervous system, heart, smooth muscle, bone, and endocrine system. [2]

Contents

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 cancer, [4] absence epilepsy, [5] pain, [6] and Parkinson's disease. [7] Further research is continuously occurring to better understand these distinct channels, as well as to create drugs to selectively target these channels.

Calcium channel, voltage-dependent, T-type, alpha 1G subunit
Identifiers
SymbolCACNA1G
IUPHAR 535
HGNC 1394
OMIM 604065
RefSeq NM_018896
UniProt O43497
Other data
Locus Chr. 17 q22
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Structures Swiss-model
Domains InterPro
Calcium channel, voltage-dependent, T-type, alpha 1H subunit
Identifiers
SymbolCACNA1H
IUPHAR 536
NCBI gene 8912
HGNC 1395
OMIM 607904
RefSeq NM_001005407
UniProt O95180
Other data
Locus Chr. 16 p13.3
Search for
Structures Swiss-model
Domains InterPro
Calcium channel, voltage-dependent, T-type, alpha 1I subunit
Identifiers
SymbolCACNA1I
IUPHAR 537
NCBI gene 8911
HGNC 1396
OMIM 608230
RefSeq NM_001003406
UniProt Q9P0X4
Other data
Locus Chr. 22 q13.1
Search for
Structures Swiss-model
Domains InterPro

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. [1] T-type calcium channels are activated in the same range as voltage-gated sodium channels, 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 and other neurotransmitters, which inhibit T-type currents. Additionally, in certain cells angiotensin II enhances the activation of T-type channels. [1]

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

Voltage-gated calcium channels are made up of several subunits. The α1 subunit is the primary subunit that forms the transmembrane pore of the channel. [1] 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. [2]

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. [1] [3] 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. [3] 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. [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.

Designationα1 SubunitGene
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, insulinoma, retinoblastoma, leukemia, ovarian, and melanoma, and they also play key roles in proliferation, survival, and the regulation of cell cycle progression 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 effects in cancer cells such as gliomas, breast, melanomas, and ovarian, esophageal, and colorectal cancers . Some of the most notorious forms of cancer tumors contain cancer stem cells (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. [6]

Epilepsy

The major disease that involves the T-type calcium channel is absence epilepsy. This disease is caused by mutations of T-type calcium channel itself. Individuals with absence seizures have brief periods of behavioral arrest and unresponsiveness. [1] 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. [5] In fact, neurons isolated from the reticular nucleus of the thalamus 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. [5] 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. [5] 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. [5] The first-line treatments for childhood absence epilepsy, valproate and ethosuximide, are both blockers of T-type calcium channels; the second-line treatment, lamotrigine, although not a T-type calcium channel blocker, does inhibit high-voltage activated calcium channels. [9]

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. [4] As mentioned above, blockage or down regulation of the T-type calcium channels causes cytostasis 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. [4] On the other hand, a combined therapy involving administration of a T-type channel antagonist followed by cytotoxic therapy is currently in its clinical trial phase. [4]

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]

Related Research Articles

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 medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are also frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, and to reduce chest pain caused by angina pectoris.

<span class="mw-page-title-main">BK channel</span> Family of transport proteins

BK channels (big potassium), are large conductance calcium-activated potassium channels, also known as Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the cell membrane, hence their name, big potassium. These channels can be activated (opened) by either electrical means, or by increasing Ca2+ concentrations in the cell. BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability. BK channels are also involved in many processes in the body, as it is a ubiquitous channel. They have a tetrameric structure that is composed of a transmembrane domain, voltage sensing domain, potassium channel domain, and a cytoplasmic C-terminal domain, with many X-ray structures for reference. Their function is to repolarize the membrane potential by allowing for potassium to flow outward, in response to a depolarization or increase in calcium levels.

An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential. The opposite of an inhibitory postsynaptic potential is an excitatory postsynaptic potential (EPSP), which is a synaptic potential that makes a postsynaptic neuron more likely to generate an action potential. IPSPs can take place at all chemical synapses, which use the secretion of neurotransmitters to create cell-to-cell signalling. EPSPs and IPSPs compete with each other at numerous synapses of a neuron. This determines whether an action potential occurring at the presynaptic terminal produces an action potential at the postsynaptic membrane. Some common neurotransmitters involved in IPSPs are GABA and glycine.

<span class="mw-page-title-main">Voltage-gated ion channel</span> Type of ion channel transmembrane protein

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in a cell's electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels.

A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, which are a type of calcium channel regulated by changes in membrane potential. Some calcium channels are regulated by the binding of a ligand. Other calcium channels can also be regulated by both voltage and ligands to provide precise control over ion flow. Some cation channels allow calcium as well as other cations to pass through the membrane.

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 permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

<span class="mw-page-title-main">Sodium channel</span> Transmembrane protein allowing sodium ions in and out

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.

<span class="mw-page-title-main">Sodium voltage-gated channel alpha subunit 9</span> Protein-coding gene in the species Homo sapiens

Sodium voltage-gated channel alpha subunit 9 is a sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at the dorsal root ganglion (DRG) and trigeminal ganglion; and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.

The P-type calcium channel is a type of voltage-dependent calcium channel. Similar to many other high-voltage-gated calcium channels, the α1 subunit determines most of the channel's properties. The 'P' signifies cerebellar Purkinje cells, referring to the channel's initial site of discovery. P-type calcium channels play a similar role to the N-type calcium channel in neurotransmitter release at the presynaptic terminal and in neuronal integration in many neuronal types.

<span class="mw-page-title-main">L-type calcium channel</span> Family of transport proteins

The L-type calcium 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 channel has four isoforms: Cav1.1, Cav1.2, Cav1.3, and Cav1.4.

Na<sub>v</sub>1.9 Protein-coding gene in the species Homo sapiens

Sodium channel, voltage-gated, type XI, alpha subunit also known as SCN11A or Nav1.9 is a voltage-gated sodium ion channel protein which is encoded by the SCN11A gene on chromosome 3 in humans. Like Nav1.7 and Nav1.8, Nav1.9 plays a role in pain perception. This channel is largely expressed in small-diameter nociceptors of the dorsal root ganglion and trigeminal ganglion neurons, but is also found in intrinsic myenteric neurons.

<span class="mw-page-title-main">KCNB1</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or Kv2.1, is a protein that, in humans, is encoded by the KCNB1 gene.

Ca<sub>v</sub>1.3 Protein found in humans

Calcium channel, voltage-dependent, L type, alpha 1D subunit is a protein that in humans is encoded by the CACNA1D gene. Cav1.3 channels belong to the Cav1 family, which form L-type calcium currents and are sensitive to selective inhibition by dihydropyridines (DHP).

Low-threshold spikes (LTS) refer to membrane depolarizations by the T-type calcium channel. LTS occur at low, negative, membrane depolarizations. They often follow a membrane hyperpolarization, which can be the result of decreased excitability or increased inhibition. LTS result in the neuron reaching the threshold for an action potential. LTS is a large depolarization due to an increase in Ca2+ conductance, so LTS is mediated by calcium (Ca2+) conductance. The spike is typically crowned by a burst of two to seven action potentials, which is known as a low-threshold burst. LTS are voltage dependent and are inactivated if the cell's resting membrane potential is more depolarized than −60mV. LTS are deinactivated, or recover from inactivation, if the cell is hyperpolarized and can be activated by depolarizing inputs, such as excitatory postsynaptic potentials (EPSP). LTS were discovered by Rodolfo Llinás and coworkers in the 1980s.

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are integral membrane proteins that serve as nonselective voltage-gated cation channels in the plasma membranes of heart and brain cells. HCN channels are sometimes referred to as pacemaker channels because they help to generate rhythmic activity within groups of heart and brain cells. HCN channels are activated by membrane hyperpolarization, are permeable to Na + and K +, and are constitutively open at voltages near the resting membrane potential. HCN channels are encoded by four genes and are widely expressed throughout the heart and the central nervous system.

<span class="mw-page-title-main">Calcium channel, voltage-dependent, T type, alpha 1H subunit</span> Protein found in humans

Calcium channel, voltage-dependent, T type, alpha 1H subunit, also known as CACNA1H, is a protein which in humans is encoded by the CACNA1H gene.

<span class="mw-page-title-main">Spike-and-wave</span>

Spike-and-wave is a pattern of the electroencephalogram (EEG) typically observed during epileptic seizures. A spike-and-wave discharge is a regular, symmetrical, generalized EEG pattern seen particularly during absence epilepsy, also known as ‘petit mal’ epilepsy. The basic mechanisms underlying these patterns are complex and involve part of the cerebral cortex, the thalamocortical network, and intrinsic neuronal mechanisms.

<span class="mw-page-title-main">Dendritic spike</span> Action potential generated in the dendrite of a neuron

In neurophysiology, a dendritic spike refers to an action potential generated in the dendrite of a neuron. Dendrites are branched extensions of a neuron. They receive electrical signals emitted from projecting neurons and transfer these signals to the cell body, or soma. Dendritic signaling has traditionally been viewed as a passive mode of electrical signaling. Unlike its axon counterpart which can generate signals through action potentials, dendrites were believed to only have the ability to propagate electrical signals by physical means: changes in conductance, length, cross sectional area, etc. However, the existence of dendritic spikes was proposed and demonstrated by W. Alden Spencer, Eric Kandel, Rodolfo Llinás and coworkers in the 1960s and a large body of evidence now makes it clear that dendrites are active neuronal structures. Dendrites contain voltage-gated ion channels giving them the ability to generate action potentials. Dendritic spikes have been recorded in numerous types of neurons in the brain and are thought to have great implications in neuronal communication, memory, and learning. They are one of the major factors in long-term potentiation.

<span class="mw-page-title-main">CACNA1G</span> Protein-coding gene in humans

Calcium channel, voltage-dependent, T type, alpha 1G subunit, also known as CACNA1G or Cav3.1 is a protein which in humans is encoded by the CACNA1G gene. It is one of the primary targets in the pharmacology of absence seizure.

References

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  2. 1 2 Iftinca MC (May 2011). "Neuronal T-type calcium channels: what's new? Iftinca: T-type channel regulation". Journal of Medicine and Life. 4 (2): 126–138. PMC   3124264 . PMID   21776294.
  3. 1 2 3 4 5 6 Perez-Reyes E (January 2003). "Molecular physiology of low-voltage-activated t-type calcium channels". Physiological Reviews. 83 (1): 117–161. doi:10.1152/physrev.00018.2002. PMID   12506128.
  4. 1 2 3 4 5 6 7 Dziegielewska B, Gray LS, Dziegielewski J (April 2014). "T-type calcium channels blockers as new tools in cancer therapies". Pflügers Archiv. 466 (4): 801–810. doi:10.1007/s00424-014-1444-z. PMID   24449277. S2CID   18238236.
  5. 1 2 3 4 5 Nelson MT, Todorovic SM, Perez-Reyes E (2006). "The role of T-type calcium channels in epilepsy and pain". Current Pharmaceutical Design. 12 (18): 2189–2197. doi:10.2174/138161206777585184. PMID   16787249.
  6. 1 2 3 4 Todorovic SM, Jevtovic-Todorovic V (April 2014). "Targeting of CaV3.2 T-type calcium channels in peripheral sensory neurons for the treatment of painful diabetic neuropathy". Pflügers Archiv. 466 (4): 701–706. doi:10.1007/s00424-014-1452-z. PMID   24482063. S2CID   15152953.
  7. 1 2 Bermejo PE, Anciones B (September 2009). "A review of the use of zonisamide in Parkinson's disease". Therapeutic Advances in Neurological Disorders. 2 (5): 313–317. doi:10.1177/1756285609338501. PMC   3002602 . PMID   21180621.
  8. 1 2 Nicholls JG, Martin AR, Fuchs PA, Brown DA, Diamond ME, Weisblat DA (2012). From neuron to brain (5th ed.). Sunderland, Mass.: Sinauer Associates. pp. 87–88. ISBN   9780878936090.
  9. ↑ Kessler SK, McGinnis E (February 2019). "A Practical Guide to Treatment of Childhood Absence Epilepsy". Paediatric Drugs. 21 (1): 15–24. doi:10.1007/s40272-019-00325-x. PMC   6394437 . PMID   30734897.
  10. ↑ Choi S, Na HS, Kim J, Lee J, Lee S, Kim D, et al. (July 2007). "Attenuated pain responses in mice lacking Ca(V)3.2 T-type channels". Genes, Brain and Behavior. 6 (5): 425–431. doi: 10.1111/j.1601-183X.2006.00268.x . PMID   16939637. S2CID   21984943.
  11. ↑ Bourinet E, Francois A, Laffray S (February 2016). "T-type calcium channels in neuropathic pain" (PDF). Pain. 157 (Suppl 1): S15–S22. doi:10.1097/j.pain.0000000000000469. PMID   26785151. S2CID   23847088.
  12. ↑ Kerckhove N, Mallet C, François A, Boudes M, Chemin J, Voets T, et al. (April 2014). "Ca(v)3.2 calcium channels: the key protagonist in the supraspinal effect of paracetamol" (PDF). Pain. 155 (4): 764–772. doi:10.1016/j.pain.2014.01.015. PMID   24447516. S2CID   5241999.
  13. ↑ Marger F, Gelot A, Alloui A, Matricon J, Ferrer JF, Barrère C, et al. (July 2011). "T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome". Proceedings of the National Academy of Sciences of the United States of America. 108 (27): 11268–11273. Bibcode:2011PNAS..10811268M. doi: 10.1073/pnas.1100869108 . PMC   3131334 . PMID   21690417.
  14. ↑ Rubin JE, McIntyre CC, Turner RS, Wichmann T (July 2012). "Basal ganglia activity patterns in parkinsonism and computational modeling of their downstream effects". The European Journal of Neuroscience. 36 (2): 2213–2228. doi:10.1111/j.1460-9568.2012.08108.x. PMC   3400124 . PMID   22805066.
  15. 1 2 Devergnas A, Chen E, Ma Y, Hamada I, Pittard D, Kammermeier S, et al. (January 2016). "Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys". Journal of Neurophysiology. 115 (1): 470–485. doi:10.1152/jn.00858.2015. PMC   4760490 . PMID   26538609.
  16. ↑ Albin RL, Young AB, Penney JB (October 1989). "The functional anatomy of basal ganglia disorders". Trends in Neurosciences. 12 (10): 366–375. doi:10.1016/0166-2236(89)90074-X. hdl: 2027.42/28186 . PMID   2479133. S2CID   8112392.
  17. ↑ Bosch-Bouju C, Hyland BI, Parr-Brownlie LC (2013-01-01). "Motor thalamus integration of cortical, cerebellar and basal ganglia information: implications for normal and parkinsonian conditions". Frontiers in Computational Neuroscience. 7: 163. doi: 10.3389/fncom.2013.00163 . PMC   3822295 . PMID   24273509.
  18. ↑ Leventhal DK, Gage GJ, Schmidt R, Pettibone JR, Case AC, Berke JD (February 2012). "Basal ganglia beta oscillations accompany cue utilization". Neuron. 73 (3): 523–536. doi:10.1016/j.neuron.2011.11.032. PMC   3463873 . PMID   22325204.
  19. ↑ Xiang Z, Thompson AD, Brogan JT, Schulte ML, Melancon BJ, Mi D, et al. (December 2011). "The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson's Disease". ACS Chemical Neuroscience. 2 (12): 730–742. doi:10.1021/cn200090z. PMC   3285241 . PMID   22368764.
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