Multiple domains contribute to the distinct inactivation properties of human heart and skeletal muscle Na+ channels

Naomasa Makita, Paul B. Bennett, Alfred L. George*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Voltage-gated Na+ channels are essential for the normal electrical excitability of neuronal and striated muscle membranes. Distinct isoforms of the Na+ channel α-subunit have been identified by molecular cloning, and their functional attributes have been defined by heterologous expression coupled with electrophysiological recording. Two closely related Na+ channel α-subunit isoforms, hH1 (human heart) and hSkM1 (human skeletal muscle), exhibit differences in their inactivation properties and in their response to the coexpressed β1-subunit. To localize regions that contribute to inactivation and to β1-subunit response, we have exploited these functional differences by studying chimeric channels composed of segments from both hH1 and hSkM1. Chimeras in which one or more of the cytoplasmic interdomain regions (ID1-2, ID2-3, and ID3-4) were exchanged between hH1 and hSkM1 exhibit inactivation properties identical with the background channel isoform, suggesting that these regions are not sufficient to cause gating differences. In contrast, inactivation properties of chimeras composed of approximately equal halves of the two channel isoforms were intermediate between hH1 and hSkM1. Furthermore, the response to the coexpressed β1-subunit was dependent on structures located in the carboxy-terminal half of the α-subunit, although domains D3, D4, and the carboxy terminal are not singularly responsible for this effect. These data indicate that inactivation differences between hH1 and hSkM1 are determined by multiple α-subunit domains.

Original languageEnglish (US)
Pages (from-to)244-252
Number of pages9
JournalCirculation research
Volume78
Issue number2
DOIs
StatePublished - Feb 1996

Keywords

  • Na channel
  • electrophysiology
  • ion channel gating

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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