Subcellular heterogeneity of sodium current properties in adult cardiac ventricular myocytes

Xianming Lin, Nian Liu, Jia Lu, Jie Zhang, Justus M.B. Anumonwo, Lori L. Isom, Glenn I. Fishman, Mario Delmar

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

Background: Sodium channel α-subunits in ventricular myocytes (VMs) segregate either to the intercalated disc or to lateral membranes, where they associate with region-specific molecules. Objective: To determine the functional properties of sodium channels as a function of their location in the cell. Methods: Local sodium currents were recorded from adult rodent VMs and Purkinje cells by using the cell-attached macropatch configuration. Electrodes were placed either in the cell midsection (M) or at the cell end (area originally occupied by the intercalated disc [ID]). Channels were identified as tetrodotoxin (TTX)-sensitive (TTX-S) or TTX-resistant (TTX-R) by application of 100 nM of TTX. Results: Average peak current amplitude was larger in ID than in M and largest at the site of contact between attached cells. TTX-S channels were found only in the M region of VMs and not in Purkinje myocytes. TTX-R channels were found in both M and ID regions, but their biophysical properties differed depending on recording location. Sodium current in rat VMs was upregulated by tumor necrosis factor-alpha. The magnitude of current increase was largest in the M region, but this difference was abolished by application of 100 nM of TTX. Conclusions: Our data suggest that (a) a large fraction of TTX-R (likely Na v1.5) channels in the M region of VMs are inactivated at normal resting potential, leaving most of the burden of excitation to TTX-R channels in the ID region; (b) cellcell adhesion increases functional channel density at the ID; and (c) TTX-S (likely non-Na v1.5) channels make a minimal contribution to sodium current under control conditions, but they represent a functional reserve that can be upregulated by exogenous factors.

Original languageEnglish
Pages (from-to)1923-1930
Number of pages8
JournalHeart Rhythm
Volume8
Issue number12
DOIs
StatePublished - Dec 2011
Externally publishedYes

Keywords

  • Intercalated disc
  • Nav1.5
  • Sodium current

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