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Molecular determinants of voltage-dependent inactivation in calcium channels

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Abstract

VOLTAGE-DEPENDENT Ca2+ channels respond to membrane depolarization by conformational changes that control channel opening and eventual closing by inactivation1–3. The kinetics of inactivation differ considerably between types of Ca2+ channels1–8 and are important in determining the amount of Ca2+ entry during electrical activity and its resulting impact on diverse cellular events3. The most intensively characterized forms of inacti-vation in potassium9–10 and sodium channels11–13 involve pore block by a tethered plug14. In contrast, little is known about the molecu-lar basis of Ca2+-channel inactivation. We studied the molecular mechanism of inactivation of voltage-gated calcium channels by making chimaeras from channels with different inactivation rates. We report here that the amino acids responsible for the kinetic differences are localized to membrane-spanning segment S6 of the first repeat of the ai subunit (IS6), and to putative extracellular and cytoplasmic domains flanking IS6. Involvement of this region in Ca2+ -channel inactivation was unexpected and raises interesting comparisons with Na+ channels, where the III-IV loop is a critical structural determinant. Ca2+ -channel inactivation has some features that resemble C-type inactivation of potassium channels.

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology,

    Ji-Fang Zhang, Patrick T. Ellinor, Richard W. Aldrich & Richard W. Tsien

  2. Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, California, 94305, USA

    Richard W. Aldrich

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  1. Ji-Fang Zhang
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  2. Patrick T. Ellinor
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  3. Richard W. Aldrich
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  4. Richard W. Tsien
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Zhang, JF., Ellinor, P., Aldrich, R. et al. Molecular determinants of voltage-dependent inactivation in calcium channels. Nature 372, 97–100 (1994). https://doi.org/10.1038/372097a0

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