Lack of the Burst Firing of Thalamocortical Relay Neurons and Resistance to Absence Seizures in Mice Lacking α1G T-Type Ca2+ Channels

Kim, Daesoo; Song, Inseon; Keum, Sehoon; Lee, Taehoon; Jeong, Myung Jin; Kim, Sung Sook; McEnery, Maureen W.; Shin, Hee Sup

doi:10.1016/s0896-6273(01)00343-9

Cited by 497 publications

(447 citation statements)

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“…Definitive proof that thalamic LTS are mediated by T-type channels was provided by studies on transgenic mice, where knockout of the Ca v 3.1 gene abolished these spikes and burst firing (Fig. 2C) (206).…”

Section: A Low-threshold Calcium Spikesmentioning

confidence: 99%

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

Perez‐Reyes

2003

Physiological Reviews

1,518

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: A Low-threshold Calcium Spikesmentioning

confidence: 99%

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

Perez‐Reyes

2003

Physiological Reviews

1,518

1,446

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“…Specific ion channels mediate the rise in [Ca 2+ ] i within sperm, and many candidates for the principle Ca 2+ channel in sperm, including various voltagegated Ca 2+ channels, were proposed based primarily on studies using Ca 2+ imaging, immunolabeling, and patch-clamp experiments from sperm precursors [61][62][63]. However, genetic ablation studies suggested that these candidate proteins were not functionally necessary for male fertility or some compensatory mechanism for their loss may be present [64][65][66][67][68]. The molecular identity of the first sperm specific ion channel required for male fertility in mice was determined in 2001 with the cloning of CatSper1 [24].…”

Section: Calcium Channels and Hyperactivationmentioning

confidence: 99%

Flagellar ion channels of sperm: similarities and differences between species

et al. 2015

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a b s t r a c tMotility and fertilization potential of mammalian sperm are regulated by ion homeostasis which in turn is under tight control of ion channels and transporters. Sperm intracellular pH, membrane voltage and calcium concentration ([Ca 2+ ] i ) are all important for sperm activity within the female reproductive tract. While all mammalian sperm are united in their goal to find and fertilize an egg, the molecular mechanisms they utilize for this purpose are diverse and differ between species especially on the level of ion channels. Recent direct recording from sperm cells of different species indicate the differences between rodent, non-human primate, ruminant, and human sperm on the basic levels of their ion channel regulation. In this review we summarize the current knowledge about ion channel diversity of the animal kingdom and concentrate our attention on flagellar ion channels of mammalian sperm.

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“…[72][73][74] As expected from this pharmacological observation, mice that lack ␣ 1G T-type Ca 2ϩ channels are resistant to absence seizures. 75,76 The three recessive mutations in Cacna1a (Ca v 2.1) that produce absence-like syndromes in tottering, leaner and rocker mice all impair channel function, reducing P/Q-type Ca 2ϩ currents. These and rolling Nagoya mice (with a further mutation on Cacna1a but not showing absence seizures) show ataxia and a wide variety of other central nervous system changes.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Lack of the Burst Firing of Thalamocortical Relay Neurons and Resistance to Absence Seizures in Mice Lacking α1G T-Type Ca2+ Channels

Abstract: Huguenard and Prince, 1994a). The hyperpolarization of membrane potentials induced by the activation of GABA B receptors evokes rebound burst discharges in TC neurons (Crunelli and Leresche, 1991; McCormick and Bal, 1994). This characteristic firing pat-

Cited by 497 publications

References 46 publications

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

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

Flagellar ion channels of sperm: similarities and differences between species

Molecular Targets for Antiepileptic Drug Development

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