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J Biol Chem, Vol. 275, Issue 9, 6090-6100, March 3, 2000

Molecular and Functional Properties of the Human _1G Subunit That Forms T-type Calcium Channels^*

Arnaud Monteil^§, Jean Chemin, Emmanuel Bourinet, Gérard Mennessier^¶, Philippe Lory, and Joël Nargeot

From  IGH-CNRS UPR 1142, 141 rue de la Cardonille, F-34396 Montpellier cedex 05, France and ^¶ CNRS, UMR 5825, Université de Montpellier II, F-34095 Montpellier cedex 05, France

We describe here several novel properties of the human _1G subunit that forms T-type calcium channels. The partial intron/exon structure of the corresponding gene CACNA1G was defined and several _1G isoforms were identified, especially two isoforms that exhibit a distinct III-IV loop: _1G-a and _1G-b. Northern blot and dot blot analyses indicated that _1G mRNA is predominantly expressed in the brain, especially in thalamus, cerebellum, and substantia nigra. Additional experiments have also provided evidence that _1G mRNA is expressed at a higher level during fetal life in nonneuronal tissues (i.e. kidney, heart, and lung). Functional expression in HEK 293 cells of a full-length cDNA encoding the shortest _1G isoform identified to date, _1G-b, resulted in transient, low threshold activated Ca²⁺ currents with the expected permeability ratio (I_Sr > I_Ca  I_Ba) and channel conductance (~7 pS). These properties, together with slowly deactivating tail currents, are typical of those of native T-type Ca²⁺ channels. This _1G-related current was inhibited by mibefradil (IC₅₀ = 2 µM) and weakly blocked by Ni²⁺ ions (IC₅₀ = 148 µM) and amiloride (IC₅₀ > 1 mM). We showed that steady state activation and inactivation properties of this current can generate a "window current" in the range of 65 to 55 mV. Using neuronal action potential waveforms, we show that _1G channels produce a massive and sustained Ca²⁺ influx due to their slow deactivation properties. These latter properties would account for the specificity of Ca²⁺ influx via T-type channels that occurs in the range of physiological resting membrane potentials, differing considerably from the behavior of other Ca²⁺ channels.

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^* This work was supported in part by the Program Génome du CNRS, Association pour la Recherche contre le Cancer Grant ARC9011, and Association Française contre les myopathies.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF126966 (_1G-a) and AF126965 (_1G-b).

^§ Supported by Produit Roche (France) and the GRRC (Groupe de Réflexion sur la Recherche Cardio-vasculaire).

To whom correspondence should be addressed. Tel.: 33 499 61 99 36; Fax: 33 499 61 99 01; E-mail: philippe.lory@igh.cnrs.fr.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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