Molecular Pharmacology of T-type Ca2+ Channels

Heady, Tiffany N.; Gómora, Juan Carlos; Macdonald, Timothy L.; Perez‐Reyes, Edward

doi:10.1254/jjp.85.339

Cited by 80 publications

(85 citation statements)

References 82 publications

(52 reference statements)

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“…These data suggest that the voltage-gated L-type Ca 2+ -channels are playing the major role in the generation of plateau potentials. Alternatively, nifedipine has an ability to inhibit T-type Ca 2+ -channels at 1 µM concentration, although this does not seem to be supported from the molecular pharmacology of Ca 2+ -channels (Mori et al, 1996;Heady et al, 2001). In summary, the effects of nifedipine and Ni 2+ on plateau potentials generated in submucosal ICC of the mouse proximal colon indicated that at subthreshold concentrations, Ni 2+ reduces the rate of rise of the initial component and nifedipine reduced the duration of the plateau component.…”

Section: Discussionmentioning

confidence: 94%

Effects of Nifedipine and Nickel on Plateau Potentials Generated in Submucosal Interstitial Cells Distributed in the Mouse Proximal Colon.

Yoneda

Takano

Takaki

et al. 2003

J Smooth Muscle Res

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The effects of nifedipine and nickel ions (Ni 2+ ), known inhibitors of L-and T-type voltage-gated Ca-channels respectively, were investigated on plateau potentials recorded from submucosal interstitial cells distributed in the mouse proximal colon. Plateau potentials were generated at a frequency of about 15 times min -1 and were formed of two components. The primary component had an initial fast rate of rise with a transient potential (rate of rise, 130 mV/s; peak amplitude, 35 mV) and was followed by a secondary plateau component with a sustained potential (amplitude, 25 mV; duration, 2.6 s). Each cell from which recordings were made was injected with neurobiotin. Subsequent morphological examination with a confocal microscope indicated successful visualization of injected cells only in the presence of 18β-glycylrhetinic acid (an inhibitor of gap junctional connections), suggesting that these cells were dye-coupled with surrounding cells. The cells injected with neurobiotin exhibited an oval-shaped cell body with bipolar processes and were distributed in the submucosal layer, suggesting that they were submucosal interstitial cells of Cajal (ICC-SM). The plateau potentials were not altered by 0.01 µM nifedipine, but were reduced in duration by 0.1 µM nifedipine, and abolished by 1 µM nifedipine. The rate of rise of plateau potentials, but not their amplitude, was reduced by Ni 2+ (> 10 µM), with no significant alteration of the membrane potential. In the presence of 100 µM Ni 2+ , the plateau potentials were changed to a triangular form. Thus, the plateau potentials were formed by two types of voltage-gated channel current: the initial component was produced by a Ni 2+ -sensitive channel current and the plateau component by a nifedipine-sensitive current. The possible involvement of two different types of voltage-gated Ca 2+ -channels in the generation of submucosal pacemaker potentials was discussed.

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Section: Discussionmentioning

confidence: 94%

Effects of Nifedipine and Nickel on Plateau Potentials Generated in Submucosal Interstitial Cells Distributed in the Mouse Proximal Colon.

Yoneda

Takano

Takaki

et al. 2003

J Smooth Muscle Res

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“…In contrast, there are no highly selective drugs or peptide toxins (369) that selectively block Ca v 3 channels. A comprehensive review of drugs tested on native T-type channels was recently published (158); therefore, this review focuses on drugs whose mechanism may involve block of T-type channels.…”

Section: Pharmacologymentioning

confidence: 99%

“…Subsequent studies required much higher concentrations for block (IC 50 ϳ200 M; reviewed in Ref. 158). Recombinant T-type channels can be totally blocked by octanol, with 50% inhibition occurring at 160 M for Ca v 3.1 and 219 M for Ca v 3.2 (404).…”

Section: Anestheticsmentioning

confidence: 99%

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

Perez‐Reyes

2003

Physiological Reviews

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1,521

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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“…Finally, selectivity of T-type VGCC blockers may account for the protective effects of trimethadione and ethosuximide. Recent studies have suggested that the blocking of ionic channels other than T-type VGCC is relevant to the antiepileptic actions of ethosuximide because most studies failed to confirm the blocking of T-type currents at therapeutically relevant concentrations of ethosuximide (Heady et al 2001). Unfortunately, no compounds that are selective for T-type VGCC have been identified so far; thus, it is uncertain whether the selective inhibition of T-type VGCC is of clinical importance in acoustic injury.…”

Section: +mentioning

confidence: 99%