An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart.
Voltage-gated sodium channels composed of pore-forming alpha and auxiliary beta subunits are responsible for the rising phase of the action potential in cardiac muscle, but the functional roles of distinct sodium channel subtypes have not been clearly defined. Immunocytochemical studies show that the principal cardiac pore-forming alpha subunit isoform Na(v)1.5 is preferentially localized in intercalated disks, whereas the brain alpha subunit isoforms Na(v)1.1, Na(v)1.3, and Na(v)1.6 are localized in the transverse tubules. Sodium currents due to the highly tetrodotoxin (TTX)-sensitive brain isoforms in the transverse tubules are small and are detectable only after activation with beta scorpion toxin. Nevertheless, they play an important role in coupling depolarization of the cell surface membrane to contraction, because low TTX concentrations reduce left ventricular function. Our results suggest that the principal cardiac isoform in the intercalated disks is primarily responsible for action potential conduction between cells and reveal an unexpected role for brain sodium channel isoforms in the transverse tubules in coupling electrical excitation to contraction in cardiac muscle.
Maier
Sebastian K G
SK
Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
Westenbroek
Ruth E
RE
Schenkman
Kenneth A
KA
Feigl
Eric O
EO
Scheuer
Todd
T
Catterall
William A
WA
D000818:Animals; D001921:Brain; D002460:Cell Line; D004553:Electric Conductivity; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D021122:Protein Subunits; D021381:Protein Transport; D012604:Scorpion Venoms / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
C115646:CSS IV toxin; D020033:Protein Isoforms; D021122:Protein Subunits; D012604:Scorpion Venoms; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D012964:Sodium