Role of the C-terminal domain in inactivation of brain and cardiac sodium channels

M. Mantegazza, F. H. Yu, W. A. Catterall, T. Scheuer

Research output: Contribution to journalArticlepeer-review

Abstract

Inactivation is a fundamental characteristic of Na+ channels, and small changes cause skeletal muscle paralysis and myotonia, epilepsy, and cardiac arrhythmia. Brain Nav1.2a channels have faster inactivation than cardiac Nav1.5 channels, but minor differences in inactivation gate structure are not responsible. We constructed chimeras in which the C termini beyond the fourth homologous domains of Nav1.2a and Nav1.5 were exchanged. Replacing the C-terminal domain (CT) of Nav1.2a with that of Nav1.5 (Nav1.2/Nav1.5CT) slowed inactivation at +40 mV ≈2-fold, making it similar to Nav1.5. Conversely, replacing the CT of Nav1.5 with that of Nav1.2a (Nav1.5/1.2CT) accelerated inactivation, making it similar to Nav1.2a. Activation properties were unaffected. The voltage dependence of steady-state inactivation of Nav1.5 is 16 mV more negative than that of Nav1.2a. The steady-state inactivation curve of Nav1.2a was shifted +12 mV in Nav1.2/1.5CT, consistent with destabilization of the inactivated state. Conversely, Nav1.5/1.2CT was shifted -14 mV relative to Nav1.5, consistent with stabilization of the inactivated state. Although these effects of exchanging C termini were consistent with their effects on inactivation kinetics, they magnified the differences in the voltage dependence of inactivation between brain and cardiac channels rather than transferring them. Thus, other parts of these channels determine the basal difference in steady-state inactivation. Deletion of the distal half of either the Nav1.2 or Nav1.5 CTs accelerated open-state inactivation and negatively shifted steady-state inactivation. Thus, the C terminus has a strong influence on kinetics and voltage dependence of inactivation in brain Nav1.2 and cardiac Nav1.5 channels and is primarily responsible for their differing rates of channel inactivation.

Original languageEnglish
Pages (from-to)15348-15353
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number26
DOIs
Publication statusPublished - Dec 18 2001

ASJC Scopus subject areas

  • Genetics
  • General

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