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Turning up the heat on L-type Ca2+ channels promotes neuronal firing and seizure activity

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Landes Bioscience

neuron, fever, hyperthermia, hippocampus, Cav1.2, nimodipine

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      Abstract

      It is well recognized clinically that fever in young children (< 6 y of age) may lead to seizure activity in a small, but significant percentage of these individuals, which may have negative consequences for the developing brain and progressive cognitive function. In rodent models, exposure of acute brain slices to hyperthermic temperatures (i.e., 38–41°C) is reported to evoke membrane depolarization and increased neuronal firing, although the underlying molecular/cellular events responsible for these phenomena are not fully understood. Elevated temperature may alter membrane excitability by influencing individual ion channels within a given neuron, or alter the behavior and connectivity of neurons and glia that operate within a local network. In the present study, Radzicki and colleagues have examined the possibility that modest increases in tissue/body temperature (up to 40.5°C) may enhance the activity of voltage-gated Ca 2+ channels, which could then promote spontaneous firing of individual neurons and greater network discharge. The results of this work indicate that fever-like temperatures positively and reversibly influence the gating properties of L-type Ca 2+ channels, and that the L-type blocker nimodipine reduces both temperature-induced increases in spontaneous neuronal firing and the incidence/duration of discharge activity in a whole animal model of febrile seizure.

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      Five different profiles of dihydropyridines in blocking T-type Ca(2+) channel subtypes (Ca(v)3.1 (alpha(1G)), Ca(v)3.2 (alpha(1H)), and Ca(v)3.3 (alpha(1I))) expressed in Xenopus oocytes.

      1,4-dihydropyridine (DHP) Ca(2+) antagonists have recently been shown to block T-type Ca(2+) channels, which may render favorable actions on cardiovascular systems. However, this evaluation remains to be done systematically for each T-type Ca(2+) channel subtype except for the Ca(v)3.1 (alpha(1G)) subtype. To address this issue at the molecular level, blocking effects of 14 kinds of DHPs (amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nitrendipine), which are clinically used for treatments of hypertension, on 3 subtypes of T-type Ca(2+) channels [Ca(v)3.2 (alpha(1H)), Ca(v)3.3 (alpha(1I)), and Ca(v)3.1 (alpha(1G))] were investigated in the Xenopus oocyte expression system using the two-microelectrode voltage-clamp technique. These 3 kinds (alpha(1H), alpha(1I) and alpha(1G)) of T-type channels were blocked by amlodipine, manidipine and nicardipine. On the other hand, azelnidipine, barnidipine, benidipine and efonidipine significantly blocked alpha(1H) and alpha(1G), but not alpha(1I) channels, while nilvadipine and nimodipine apparently blocked alpha(1H) and alpha(1I), but not alpha(1G) channels. Moreover, aranidipine blocked only alpha(1H) channels. By contrast, cilnidipine, felodipine, nifedipine and nitrendipine had little effects on these subtypes of T-type channels. The result indicates that the blockade of T-type Ca(2+) channels by derivatives of DHP Ca(2+) antagonist was selective for the channel subtype. Therefore, these selectivities of DHPs in blocking T-type Ca(2+) channel subtypes would provide useful pharmacological and clinical information on the mode of action of the drugs including side-effects and adverse effects.
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        Author and article information

        Affiliations
        Department of Physiology and Pharmacology; Faculty of Medicine; University of Calgary; Calgary, AB Canada
        Author notes
        [* ]Correspondence to: Andrew P Braun, Email: abraun@ 123456ucalgary.ca
        Journal
        Channels (Austin)
        Channels (Austin)
        CHAN
        Channels
        Landes Bioscience
        1933-6950
        1933-6969
        01 July 2013
        29 July 2013
        29 July 2013
        : 7
        : 4
        : 229-230
        3989350 2013CHANNELS7-4-Braun 10.4161/chan.25956 25956
        Copyright © 2013 Landes Bioscience

        This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

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        Molecular biology

        nimodipine, cav1.2, hippocampus, hyperthermia, fever, neuron

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