Localization of sodium channels in intercalated disks modulates cardiac conduction.
It is well known that the sodium current (I(Na)) and the degree of gap-junctional electrical coupling are the key determinants of action potential (AP) conduction in cardiac tissue. Immunohistochemical studies have shown that sodium channels (NaChs) are preferentially located in intercalated disks (IDs). Using dual immunocytochemical staining, we confirmed the colocalization of NaChs with connexin43 in cultures of neonatal rat ventricular myocytes. In mathematical simulations of conduction using the Luo-Rudy dynamic model of the ventricular AP, we assessed the hypothesis that conduction could be modulated by the preferential localization of NaChs in IDs. Localization of I(Na) at the ID caused a large negative potential in the intercellular cleft, which influenced conduction in two opposing ways, depending on the degree of electrical coupling: (1) for normal and moderately reduced coupling, the negative cleft potential led to a large overshoot of the transmembrane potential resulting in a decreased driving force for I(Na) itself (self-attenuation), which slowed conduction; (2) for greatly reduced coupling (<10%), the negative cleft potential induced by I(Na) in the prejunctional membrane led to suprathreshold depolarization of the postjunctional membrane, which facilitated and accelerated conduction. When cleft potential effects were not incorporated, conduction was not significantly affected by the ID localization of I(Na). By enhancing conduction through the establishment of cleft potentials, the localization of NaChs in IDs might protect the myocardium from conduction block, very slow conduction, and microreentry under conditions of greatly reduced coupling. Conversely, by supporting moderately slow conduction, this mechanism could also promote arrhythmias.
Kucera
Jan P
JP
Department of Physiology, University of Bern, Switzerland. kucera@pyl.unibe.ch
Rohr
Stephan
S
Rudy
Yoram
Y
D000818:Animals; D002478:Cells, Cultured; D003198:Computer Simulation; D018031:Connexin 43 / Q000378:metabolism; D022062:Electrophysiologic Techniques, Cardiac; D017629:Gap Junctions / Q000378:metabolism; D006329:Heart Conduction System / Q000502:physiology*; D007150:Immunohistochemistry; D008564:Membrane Potentials / Q000502:physiology; D008955:Models, Cardiovascular; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000378:metabolism*
D018031:Connexin 43; D015222:Sodium Channels