This Article Full Text Full Text (PDF) All Versions of this Article: 91/12/1176    most recent 01.RES.0000046237.54156.0Av1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kucera, J. P. Articles by Rudy, Y. Search for Related Content PubMed PubMed Citation Articles by Kucera, J. P. Articles by Rudy, Y. Related Collections Structure Arrythmias-basic studies Ion channels/membrane transport Quantitative modeling

Localization of Sodium Channels in Intercalated Disks Modulates Cardiac Conduction

From the Department of Physiology (J.P.K., S.R.), University of Bern, Switzerland; Cardiac Bioelectricity Research and Training Center (Y.R.), Departments of Biomedical Engineering, Physiology & Biophysics, and Medicine, Case Western Reserve University, Cleveland, Ohio.

Correspondence to Jan P. Kucera, Department of Physiology, University of Bern, Bühlplatz 5, CH-3012 Bern, Switzerland. E-mail kucera{at}pyl.unibe.ch

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.

Key Words: action potential conduction • sodium current • gap junctions • intercalated disks • slow conduction

This article has been cited by other articles:

				Y. Mori, G. I. Fishman, and C. S. Peskin Ephaptic conduction in a cardiac strand model with 3D electrodiffusion PNAS, April 29, 2008; 105(17): 6463 - 6468. [Abstract] [Full Text] [PDF]

				J. S. Lowe, O. Palygin, N. Bhasin, T. J. Hund, P. A. Boyden, E. Shibata, M. E. Anderson, and P. J. Mohler Voltage-gated Nav channel targeting in the heart requires an ankyrin-G dependent cellular pathway J. Cell Biol., January 10, 2008; 180(1): 173 - 186. [Abstract] [Full Text] [PDF]

				S. Rohr Molecular Crosstalk Between Mechanical and Electrical Junctions at the Intercalated Disc Circ. Res., September 28, 2007; 101(7): 637 - 639. [Full Text] [PDF]

				E. M. Oxford, H. Musa, K. Maass, W. Coombs, S. M. Taffet, and M. Delmar Connexin43 Remodeling Caused by Inhibition of Plakophilin-2 Expression in Cardiac Cells Circ. Res., September 28, 2007; 101(7): 703 - 711. [Abstract] [Full Text] [PDF]

				D. F. Steele, J. Eldstrom, and D. Fedida Mechanisms of cardiac potassium channel trafficking J. Physiol., July 1, 2007; 582(1): 17 - 26. [Abstract] [Full Text] [PDF]

				S. Baba, W. Dun, C. Cabo, and P. A. Boyden Remodeling in Cells From Different Regions of the Reentrant Circuit During Ventricular Tachycardia Circulation, October 18, 2005; 112(16): 2386 - 2396. [Abstract] [Full Text] [PDF]

				J. M. Nerbonne and R. S. Kass Molecular Physiology of Cardiac Repolarization Physiol Rev, October 1, 2005; 85(4): 1205 - 1253. [Abstract] [Full Text] [PDF]

				M. Lei, C. Goddard, J. Liu, A.-L. Leoni, A. Royer, S. S.-M. Fung, G. Xiao, A. Ma, H. Zhang, F. Charpentier, et al. Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel gene Scn5a J. Physiol., September 1, 2005; 567(2): 387 - 400. [Abstract] [Full Text] [PDF]

				V. Haufe, J. A. Camacho, R. Dumaine, B. Gunther, C. Bollensdorff, G. S. von Banchet, K. Benndorf, and T. Zimmer Expression pattern of neuronal and skeletal muscle voltage-gated Na+ channels in the developing mouse heart J. Physiol., May 1, 2005; 564(3): 683 - 696. [Abstract] [Full Text] [PDF]

				V. Haufe, J.M. Cordeiro, T. Zimmer, Y.S. Wu, S. Schiccitano, K. Benndorf, and R. Dumaine Contribution of neuronal sodium channels to the cardiac fast sodium current INa is greater in dog heart Purkinje fibers than in ventricles Cardiovasc Res, January 1, 2005; 65(1): 117 - 127. [Abstract] [Full Text] [PDF]

				P. J. Mohler, I. Rivolta, C. Napolitano, G. LeMaillet, S. Lambert, S. G. Priori, and V. Bennett Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes PNAS, December 14, 2004; 101(50): 17533 - 17538. [Abstract] [Full Text] [PDF]

				X. F. Figueroa, B. E. Isakson, and B. R. Duling Connexins: Gaps in Our Knowledge of Vascular Function Physiology, October 1, 2004; 19(5): 277 - 284. [Abstract] [Full Text] [PDF]

				K. Maass, A. Ghanem, J.-S. Kim, M. Saathoff, S. Urschel, G. Kirfel, R. Grummer, M. Kretz, T. Lewalter, K. Tiemann, et al. Defective Epidermal Barrier in Neonatal Mice Lacking the C-Terminal Region of Connexin43 Mol. Biol. Cell, October 1, 2004; 15(10): 4597 - 4608. [Abstract] [Full Text] [PDF]

				J. D. Malhotra, V. Thyagarajan, C. Chen, and L. L. Isom Tyrosine-phosphorylated and Nonphosphorylated Sodium Channel {beta}1 Subunits Are Differentially Localized in Cardiac Myocytes J. Biol. Chem., September 24, 2004; 279(39): 40748 - 40754. [Abstract] [Full Text] [PDF]

				B. London Staying Connected Without Connexin43: Can You Hear Me Now? Circ. Res., July 23, 2004; 95(2): 120 - 121. [Full Text] [PDF]

				S. Rohr Role of gap junctions in the propagation of the cardiac action potential Cardiovasc Res, May 1, 2004; 62(2): 309 - 322. [Abstract] [Full Text] [PDF]

				B. G. Petrich, B. C. Eloff, D. L. Lerner, A. Kovacs, J. E. Saffitz, D. S. Rosenbaum, and Y. Wang Targeted Activation of c-Jun N-terminal Kinase in Vivo Induces Restrictive Cardiomyopathy and Conduction Defects J. Biol. Chem., April 9, 2004; 279(15): 15330 - 15338. [Abstract] [Full Text] [PDF]

				Y. Rudy Conductive Bridges in Cardiac Tissue: A Beneficial Role or an Arrhythmogenic Substrate? Circ. Res., April 2, 2004; 94(6): 709 - 711. [Full Text] [PDF]

				A. G. KLEBER and Y. RUDY Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias Physiol Rev, April 1, 2004; 84(2): 431 - 488. [Abstract] [Full Text] [PDF]

				J.-A. Yao, D. E. Gutstein, F. Liu, G. I. Fishman, and A. L. Wit Cell Coupling Between Ventricular Myocyte Pairs From Connexin43-Deficient Murine Hearts Circ. Res., October 17, 2003; 93(8): 736 - 743. [Abstract] [Full Text] [PDF]

				A. G. Kleber Cell-to-Cell Coupling Between Host and Donor Cells in the In Situ Myocardium Circ. Res., June 13, 2003; 92(11): 1176 - 1178. [Full Text] [PDF]