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(Circulation. 2004;109:1421-1427.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Distinct Subcellular Localization of Different Sodium Channel and ß Subunits in Single Ventricular Myocytes From Mouse Heart

Sebastian K.G. Maier, MD; Ruth E. Westenbroek, PhD; Kimberly A. McCormick, PhD; Rory Curtis, PhD; Todd Scheuer, PhD; William A. Catterall, PhD

From the Department of Pharmacology, University of Washington, Seattle (S.K.G.M. R.E.W., K.A.M., T.S., W.A.C.); Medizinische Universitätsklinik Würzburg, Würzburg, Germany (S.K.G.M.); and Elixir Pharmaceuticals, Cambridge, Mass (R.C.).

Correspondence to William A. Catterall, PhD, Department of Pharmacology, Box 357280, University of Washington, Seattle, WA 98195-7280. E-mail wcatt{at}u.washington.edu

Received November 21, 2002; de novo received September 19, 2003; revision received December 5, 2003; accepted December 9, 2003.

Background— Voltage-gated sodium channels composed of pore-forming and auxiliary ß subunits are responsible for the rising phase of the action potential in cardiac muscle, but their localizations have not yet been clearly defined.

Methods and Results— Immunocytochemical studies show that the principal cardiac subunit isoform Na_v1.5 and the ß2 subunit are preferentially localized in intercalated disks, identified by immunostaining of connexin 43, the major protein of cardiac gap junctions. The brain subunit isoforms Na_v1.1, Na_v1.3, and Na_v1.6 are preferentially localized with ß1 and ß3 subunits in the transverse tubules, identified by immunostaining of -actinin, a cardiac z-line protein. The ß1 subunit is also present in a small fraction of intercalated disks. The recently cloned ß4 subunit, which closely resembles ß2 in amino acid sequence, is also expressed in ventricular myocytes and is localized in intercalated disks as are ß2 and Na_v1.5.

Conclusions— Our results suggest that the primary sodium channels present in ventricular myocytes are composed of Na_v1.5 plus ß2 and/or ß4 subunits in intercalated disks and Na_v1.1, Na_v1.3, and Na_v1.6 plus ß1 and/or ß3 subunits in the transverse tubules.

Key Words: ion channels • sodium • myocytes • ventricles • immunohistochemistry

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