Critical roles of the S3 segment and S3-S4 linker of repeat I in activation of L-type calcium channels

Junichi Nakai, Brett A. Adams, Keiji Imoto, Kurt G. Beam

Research output: Contribution to journalArticlepeer-review

81 Citations (Scopus)

Abstract

Each of the four repeats (or motifs) of voltage-gated ion channels is thought to contain six transmembrane segments (S1-S6). Mutational analyses indicate that S4 functions as a voltage sensor and that the S5, S6, and S5- S6 linker contribute to formation of the ion pore. However, little information exists regarding the functional role(s) of the amino-terminal portion (S1-S3-S4 linker) of the repeats. Here we report that the amino acid composition of the S3 segment of repeat I and the linker connecting S3 and S4 segments of repeat I is critical for the difference in activation kinetics between cardiac and skeletal muscle L-type calcium channels. Mutant dihydropyridine receptors that have the skeletal muscle dihydropyridine receptor sequence in this region activated relatively slowly with the time constant of current activation (τ(act)) > 5 ms, whereas mutants that have the cardiac counterpart there activated relatively rapidly with τ(act) < 5 ms. Comparison of these two mutant groups indicates that a total of 11 conservative and 10 nonconservative amino acid changes from skeletal muscle to cardiac dihydropyridine receptor sequence are sufficient to convert activation from slow to fast. These data demonstrate a functional role for this region of voltage-gated ion channels.

Original languageEnglish
Pages (from-to)1014-1018
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number3
DOIs
Publication statusPublished - 1994 Feb 1
Externally publishedYes

Keywords

  • dihydropyridine receptor
  • heart
  • skeletal muscle

ASJC Scopus subject areas

  • General

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