Molecular determinants of L-type Ca2+ channel inactivation: Segment exchange analysis of the carboxyl-terminal cytoplasmic motif encoded by exons 40-42 of the human α(1C) subunit gene

Nikolai M. Soldatov, Murat Oz, Kathleen A. O'Brien, Darrell R. Abernethy, Martin Morad

Research output: Contribution to journalArticle

Abstract

Recently we have described a splice variant of the L-type Ca2+ channel (α(1C,86)) in which 80 amino acids (1572-1651) of the conventional α(1C,77) were substituted by another 81 amino acids due to alternative splicing of exons 40-42. Ba2+ current (I(Ba)) through α(1C,86) exhibited faster inactivation kinetics, was strongly voltage-dependent, and had no Ca2+ - dependent inactivation. An oligonucleotide-directed segment substitution and expression of the mutated channels in Xenopus oocytes were used to study the molecular determinants for gating of the channel within the 80-amino acid domain. Replacement of segments 1572-1598 or 1595-1652 of the 'slow' α(1C,77) channel with the respective segments of the 'fast' α(1C,86) gave rise to rapidly inactivating α(1C,86) like channel isoforms. We found that replacement of either motifs 1572IKTEG1576 or 1600LLDQV1604 of α(1C,77) with the respective sequences of α(1C,86) caused strong but partial acceleration of I(Ba) inactivation. Replacement of both sequences produced an α(1C,86)-like fast channel which had no Ca2+ -dependent inactivation. These results support the hypothesis that motifs 1572-1576 and 1600-1604 of α(1C,77) contribute cooperatively to inactivation kinetics of α(1C) and are critical for Ca2+ -dependent inactivation of the channel.

Original languageEnglish (US)
Pages (from-to)957-963
Number of pages7
JournalJournal of Biological Chemistry
Volume273
Issue number2
DOIs
StatePublished - Jan 9 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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