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      Neuronal T–type calcium channels: What's new? Iftinca: T–type channel regulation

      review-article
      Journal of Medicine and Life
      Carol Davila University Press
      calcium channel, T–type, sleep, pain, epilepsy

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          Abstract

          This review summarizes recent advances in our understanding of neuronal T–type calcium channel regulation as well as their physiological and pathophysiological roles. Through their ability to conduct calcium across the cellular membrane at potentials close to the resting potential, T–type calcium channels are critically important for regulating neuronal excitability, both in the central and peripheral nervous system. T–type channels are also linked to an increasing number of neurological disorders such as the absence epilepsy and neuropathic pain. Although there is substantial literature dealing with regulation of native T–type channels, the underlying molecular mechanism has only recently been addressed. It is, therefore, critical to understand the cellular mechanisms that control T–type channel activity and expression, because this could provide important insight into designing novel therapeutic strategies targeting these channels.

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          Most cited references119

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          Calcium signaling.

          Calcium ions (Ca(2+)) impact nearly every aspect of cellular life. This review examines the principles of Ca(2+) signaling, from changes in protein conformations driven by Ca(2+) to the mechanisms that control Ca(2+) levels in the cytoplasm and organelles. Also discussed is the highly localized nature of Ca(2+)-mediated signal transduction and its specific roles in excitability, exocytosis, motility, apoptosis, and transcription.
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            Molecular physiology of low-voltage-activated t-type calcium channels.

            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 alpha1-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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              Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling.

              Lysophosphatidic acid (LPA) is a bioactive lipid with activity in the nervous system mediated by G-protein-coupled receptors. Here, we examined the role of LPA signaling in the development of neuropathic pain by pharmacological and genetic approaches, including the use of mice lacking the LPA(1) receptor. Wild-type animals with nerve injury develop behavioral allodynia and hyperalgesia paralleled by demyelination in the dorsal root and increased expression of both the protein kinase C gamma-isoform within the spinal cord dorsal horn and the alpha(2)delta(1) calcium channel subunit in dorsal root ganglia. Intrathecal injection of LPA induced behavioral, morphological and biochemical changes similar to those observed after nerve ligation. In contrast, mice lacking a single LPA receptor (LPA(1), also known as EDG2) that activates the Rho-Rho kinase pathway do not develop signs of neuropathic pain after peripheral nerve injury. Inhibitors of Rho and Rho kinase also prevented these signs of neuropathic pain. These results imply that receptor-mediated LPA signaling is crucial in the initiation of neuropathic pain.
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                Author and article information

                Journal
                J Med Life
                JMedLife
                Journal of Medicine and Life
                Carol Davila University Press (Romania )
                1844-122X
                1844-3117
                15 May 2011
                25 May 2011
                : 4
                : 2
                : 126-138
                Affiliations
                simpleFoothills Medical Centre, Department of Pathology, Calgary Canada
                Author notes
                Correspondence to:Iftinca Mircea Constantin, MD, PhD, Foothills Medical Centre, Department of Pathology, 1403, 29 St, NW, Calgary, AB, T2N 2T9, Canada , e-mail Mircea.Iftinca@ 123456cls.ab.ca
                Article
                JMedLife-04-126
                3124264
                21776294
                2ec888d5-8ca2-43a7-9706-db91f71e86c7
                ©Carol Davila University Press

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 04 February 2011
                : 12 May 2011
                Categories
                Review

                Medicine
                epilepsy,sleep,pain,t–type,calcium channel
                Medicine
                epilepsy, sleep, pain, t–type, calcium channel

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