Different action of ethosuximide on low- and high-threshold calcium currents in rat sensory neurons

Kostyuk, P. G.; Molokanova, Elena; Pronchuk, Nina; Savchenko, A.; Verkhratsky, Alexei

doi:10.1016/0306-4522(92)90515-4

Cited by 82 publications

(20 citation statements)

References 9 publications

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“…Support for this hypothesis came from the following studies with related analogs: 1) T-type current block was also observed at therapeutically relevant concentrations of methyl-phenylsuccinimide (MPS), the active metabolite of the antiepileptic drug methsuximide, and 2) no block was observed using either the inactive analog succinimide or the convulsant analog tetra-methylsuccinimide (87). With one exception (215), most studies have failed to confirm ethosuximide block of T-type currents at therapeutically relevant concentrations (403), leading to the suggestion that block of other ionic channels may be more relevant (232).…”

Section: B Antiepilepticsmentioning

confidence: 99%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,506

1,446

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T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

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Section: B Antiepilepticsmentioning

confidence: 99%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,506

1,446

View full text Add to dashboard Cite

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“…The sensitivity of T-type channels to MPS has been confirmed in many other systems, including the cloned channels (Table 2). With one notable exception (44), most studies have failed to confirm block of T-type currents at therapeutically relevant concentrations, leading to the suggestion that block of other ionic channels may be more relevant (45).…”

Section: Antiepilepticsmentioning

confidence: 99%

Molecular Pharmacology of T-type Ca2+ Channels

Heady

Gómora

Macdonald

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-Over the past few years increasing attention has been focused on T-type calcium channels and their possible physiological and pathophysiological roles. Efforts toward elucidating the exact role(s) of these calcium channels have been hampered by the lack of T-type specific antagonists, resulting in the subsequent use of less selective calcium channel antagonists. In addition, the activity of these blockers often varies with cell or tissue type, as well as recording conditions. This review summarizes a variety of compounds that exhibit varying degrees of blocking activity towards T-type Ca 2+ channels. It is designed as an aid for researchers in need of antagonists to study the biophysical and pathological nature of T-type channels, as well as a starting point for those attempting to develop potent and selective antagonists of the channel.

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“…Indeed, reticular thalamic neurons are endowed with large T-type currents that mediate bursting behavior associated with SWDs. The critical role of T-type channels in SWD epilepsies is also supported by treatment of absence seizures using ethosuximide, an inhibitor of T-type Ca 2ϩ currents (10,11), and by the observation that expression of these channels is increased in thalamic neurons in a genetic rat absence model (12).…”

mentioning

confidence: 96%

Gating Effects of Mutations in the Cav3.2 T-type Calcium Channel Associated with Childhood Absence Epilepsy

Khosravani

Altier

Simms

et al. 2004

Journal of Biological Chemistry

169

100

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Childhood absence epilepsy (CAE) is a type of gener-We have functionally characterized five of these mutations (F161L, E282K, C456S, V831M, and D1463N) using rat Ca v 3.2 and whole-cell patch clamp recordings in transfected HEK293 cells. Two of the mutations, F161L and E282K, mediated an ϳ10-mV hyperpolarizing shift in the half-activation potential. Mutation V831M caused a ϳ50% slowing of inactivation relative to control and shifted half-inactivation potential ϳ10 mV toward more depolarized potentials. Mean time to peak was significantly increased by mutation V831M but was unchanged for all others. No resolvable changes in the parameters of the IV relation or current kinetics were observed with the remaining mutations. The findings suggest that several of the Ca v 3.2 mutants allow for greater calcium influx during physiological activation and in the case of F161L and E282K can result in channel openings at more hyperpolarized (close to resting) potentials. This may underlie the propensity for seizures in patients with CAE.Generalized epileptic disorders involve both brain hemispheres and are characterized by abnormal synchronous electrical (electroencephalographic) activity, recorded bilaterally at seizure onset (1). Childhood absence epilepsy (CAE) 1 is a type of idiopathic generalized epilepsy and is typified by sudden brief impairment of consciousness followed by ϳ3-Hz spikeand-wave discharges (SWDs) over both brain hemispheres (2). A typical absence seizure is without convulsions and there are no reported neuropathological changes associated with this disorder (3). Spike-wave discharges in absence epilepsy involve interactions between cortical and thalamic structures (4). The classical view of SWD-based seizures, including absence epilepsy, implicates the thalamus as the site of seizure generation (5, 6). Recently, an increasing body of evidence suggests that spike-wave seizures are initiated in the neocortex and then rapidly progress to involve thalamic structures (7-9). The thalamus and cortex then engage in complex interplay that underlies SWD generation and is dependent on the activation of low voltage-activated (T-type) calcium channels (4). Indeed, reticular thalamic neurons are endowed with large T-type currents that mediate bursting behavior associated with SWDs. The critical role of T-type channels in SWD epilepsies is also supported by treatment of absence seizures using ethosuximide, an inhibitor of T-type Ca 2ϩ currents (10, 11), and by the observation that expression of these channels is increased in thalamic neurons in a genetic rat absence model (12).We now know of three genes (subtypes) encoding different types of T-type channels (Ca v 3.1, Ca v 3.2, and Ca v 3.3), all of which are subject to alternative splicing resulting in a range of different isoforms with distinct biophysical, modulatory, and pharmacological properties (13-23). It was recently shown that Ca v 3.1 knock-out mice display reduced burst mode firing activity, and that the Ca v 3.1-deficient thalamus is specifically resilie...

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Different action of ethosuximide on low- and high-threshold calcium currents in rat sensory neurons

Cited by 82 publications

References 9 publications

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Molecular Pharmacology of T-type Ca2+ Channels

Gating Effects of Mutations in the Cav3.2 T-type Calcium Channel Associated with Childhood Absence Epilepsy

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