HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by London, B. Articles by Bennett, P. B. Search for Related Content PubMed PubMed Citation Articles by London, B. Articles by Bennett, P. B.

The transient outward current in mice lacking the potassium channel gene Kv1.4

Barry London *, Dao W. Wang ², Joseph A. Hill ¹ and Paul B. Bennett ²

1. The transient outward current (I_to) plays a prominent role in the repolarization phase of the cardiac action potential. Several K⁺ channel genes, including Kv1.4, are expressed in the heart, produce rapidly inactivating currents when heterologously expressed, and may be the molecular basis of I_to.

2. We engineered mice homozygous for a targeted disruption of the K⁺ channel gene Kv1.4 and compared I_to in wild-type (Kv1.4^+/+), heterozygous (Kv1.4^+/-) and homozygous 'knockout' (Kv1.4^-/-) mice. Kv1.4 RNA was truncated in Kv1.4^-/- mice and protein expression was absent.

3. Adult myocytes isolated from Kv1.4^+/+, Kv1.4^+/- and Kv1.4^-/- mice had large rapidly inactivating outward currents. The peak current densities at 60 mV (normalized by cellular capacitance, in pA pF^-1; means ± s.e.m.) were 53·8 ± 5·3, 45·3 ± 2·2 and 44·4 ± 2·8 in cells from Kv1.4^+/+, Kv1.4^+/- and Kv1.4^-/- mice, respectively (P < 0·02 for Kv1.4^+/+ vs. Kv1.4^-/-). The steady-state values (800 ms after the voltage clamp step) were 30·9 ± 2·9, 26·9 ± 3·8 and 23·5 ± 2·2, respectively (P < 0·02 for Kv1.4^+/+ vs. Kv1.4^-/-). The inactivating portion of the current was unchanged in the targeted mice.

4. The voltage dependence and time course of inactivation were not changed by targeted disruption of Kv1.4. The mean best-fitting V_½ (membrane potential at 50 % inactivation) values for myocytes from Kv1.4 ^+/+, Kv1.4^+/- and Kv1.4^-/- mice were -53·5 ± 3·7, -51·1 ± 2·6 and -54·2 ± 2·4 mV, respectively. The slope factors (k) were -10·1 ± 1·4, -8·8 ± 1·4 and -9·5 ± 1·2 mV, respectively. The fast time constants for development of inactivation at -30 mV were 27·8 ± 2·2, 26·2 ± 5·1 and 19·6 ± 2·1 ms in Kv1.4^+/+, Kv1.4^+/- and Kv1.4^-/- myocytes, respectively. At +30 mV, they were 35·5 ± 2·6, 30·0 ± 2·1 and 28·7 ± 1·6 ms, respectively. The time constants for the rapid phase of recovery from inactivation at -80 mV were 32·5 ± 8·2, 23·3 ± 1·8 and 39·0 ± 3·7 ms, respectively.

5. Nearly the entire inactivating component as well as more than 60 % of the steady-state outward current was eliminated by 1 mM 4-aminopyridine in Kv1.4^+/+, Kv1.4^+/- and Kv1.4^-/- myocytes.

6. Western blot analysis of heart membrane extracts showed no significant upregulation of the Kv4 subfamily of channels in the targeted mice.

7. Thus, Kv1.4 is not the molecular basis of I_to in adult murine ventricular myocytes.

This article has been cited by other articles:

				M. E. Mangoni and J. Nargeot Genesis and Regulation of the Heart Automaticity Physiol Rev, July 1, 2008; 88(3): 919 - 982. [Abstract] [Full Text] [PDF]

				S. A. Grandy, V. Trepanier-Boulay, and C. Fiset Postnatal development has a marked effect on ventricular repolarization in mice Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2168 - H2177. [Abstract] [Full Text] [PDF]

				H. M. Brew, J. X. Gittelman, R. S. Silverstein, T. D. Hanks, V. P. Demas, L. C. Robinson, C. A. Robbins, J. McKee-Johnson, S. Y. Chiu, A. Messing, et al. Seizures and Reduced Life Span in Mice Lacking the Potassium Channel Subunit Kv1.2, but Hypoexcitability and Enlarged Kv1 Currents in Auditory Neurons J Neurophysiol, September 1, 2007; 98(3): 1501 - 1525. [Abstract] [Full Text] [PDF]

				G. Salama and B. London Mouse models of long QT syndrome J. Physiol., January 1, 2007; 578(1): 43 - 53. [Abstract] [Full Text] [PDF]

				B. London, L. C. Baker, P. Petkova-Kirova, J. M. Nerbonne, B.-R. Choi, and G. Salama Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT J. Physiol., January 1, 2007; 578(1): 115 - 129. [Abstract] [Full Text] [PDF]

				M. A.G. van der Heyden, T. J.M. Wijnhoven, and T. Opthof Molecular aspects of adrenergic modulation of the transient outward current Cardiovasc Res, August 1, 2006; 71(3): 430 - 442. [Abstract] [Full Text] [PDF]

				S. P. Patel and D. L. Campbell Transient outward potassium current, 'Ito', phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms J. Physiol., November 15, 2005; 569(1): 7 - 39. [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]

				J. V. Tranquillo, J. Hlavacek, and C. S. Henriquez An integrative model of mouse cardiac electrophysiology from cell to torso Europace, January 1, 2005; 7(s2): S56 - S70. [Abstract] [Full Text] [PDF]

				V. Trepanier-Boulay, M.-A. Lupien, C. St-Michel, and C. Fiset Postnatal development of atrial repolarization in the mouse Cardiovasc Res, October 1, 2004; 64(1): 84 - 93. [Abstract] [Full Text] [PDF]

				J. Brouillette, R. B. Clark, W. R. Giles, and C. Fiset Functional properties of K+ currents in adult mouse ventricular myocytes J. Physiol., September 15, 2004; 559(3): 777 - 798. [Abstract] [Full Text] [PDF]

				H. Li, W. Guo, K. A. Yamada, and J. M. Nerbonne Selective elimination of IK,slow1 in mouse ventricular myocytes expressing a dominant negative Kv1.5{alpha} subunit Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H319 - H328. [Abstract] [Full Text] [PDF]

				I. Bodi, J. N. Muth, H. S. Hahn, N. N. Petrashevskaya, M. Rubio, S. E. Koch, G. Varadi, and A. Schwartz Electrical remodeling in hearts from a calcium-dependent mouse model of hypertrophy and failure: Complex nature of k+ current changes and action potential duration J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1611 - 1622. [Abstract] [Full Text] [PDF]

				N. N Petrashevskaya, I. Bodi, M. Rubio, J. D Molkentin, and A. Schwartz Cardiac function and electrical remodeling of the calcineurin-overexpressed transgenic mouse Cardiovasc Res, April 1, 2002; 54(1): 117 - 132. [Abstract] [Full Text] [PDF]

				Z. Kassiri, C. Zobel, T.-T. T. Nguyen, J. D. Molkentin, and P. H. Backx Reduction of Ito Causes Hypertrophy in Neonatal Rat Ventricular Myocytes Circ. Res., March 22, 2002; 90(5): 578 - 585. [Abstract] [Full Text] [PDF]

				S. Ohya, K. Asakura, K. Muraki, M. Watanabe, and Y. Imaizumi Molecular and functional characterization of ERG, KCNQ, and KCNE subtypes in rat stomach smooth muscle Am J Physiol Gastrointest Liver Physiol, February 1, 2002; 282(2): G277 - G287. [Abstract] [Full Text] [PDF]

				M. H. Holmqvist, J. Cao, R. Hernandez-Pineda, M. D. Jacobson, K. I. Carroll, M. A. Sung, M. Betty, P. Ge, K. J. Gilbride, M. E. Brown, et al. Elimination of fast inactivation in Kv4 A-type potassium channels by an auxiliary subunit domain PNAS, January 22, 2002; 99(2): 1035 - 1040. [Abstract] [Full Text] [PDF]

				J. M. Nerbonne, C. G. Nichols, T. L. Schwarz, and D. Escande Genetic Manipulation of Cardiac K+ Channel Function in Mice: What Have We Learned, and Where Do We Go From Here? Circ. Res., November 23, 2001; 89(11): 944 - 956. [Abstract] [Full Text] [PDF]

				H. Li, W. Guo, H. Xu, R. Hood, A. T. Benedict, and J. M. Nerbonne Functional expression of a GFP-tagged Kv1.5 alpha -subunit in mouse ventricle Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1955 - H1967. [Abstract] [Full Text] [PDF]

				M. Brunner, W. Guo, G. F. Mitchell, P. D. Buckett, J. M. Nerbonne, and G. Koren Characterization of mice with a combined suppression of Ito and IK,slow Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1201 - H1209. [Abstract] [Full Text] [PDF]

				M. J. Hernandez-Benito, R. Macianskiene, K. R. Sipido, W. Flameng, and K. Mubagwa Suppression of Transient Outward Potassium Currents in Mouse Ventricular Myocytes by Imidazole Antimycotics and by Glybenclamide J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 598 - 606. [Abstract] [Full Text] [PDF]

				C. A. Ufret-Vincenty, D. J. Baro, and L. F. Santana Differential contribution of sialic acid to the function of repolarizing K+ currents in ventricular myocytes Am J Physiol Cell Physiol, August 1, 2001; 281(2): C464 - C474. [Abstract] [Full Text] [PDF]

				M. H. Holmqvist, J. Cao, M. H. Knoppers, M. E. Jurman, P. S. Distefano, K. J. Rhodes, Y. Xie, and W. F. An Kinetic Modulation of Kv4-Mediated A-Current by Arachidonic Acid Is Dependent on Potassium Channel Interacting Proteins J. Neurosci., June 15, 2001; 21(12): 4154 - 4161. [Abstract] [Full Text] [PDF]

				W. Guo, H. Li, B. London, and J. M. Nerbonne Functional Consequences of Elimination of Ito, f and Ito, s : Early Afterdepolarizations, Atrioventricular Block, and Ventricular Arrhythmias in Mice Lacking Kv1.4 and Expressing a Dominant-Negative Kv4 {alpha} Subunit Circ. Res., July 7, 2000; 87(1): 73 - 79. [Abstract] [Full Text] [PDF]

				W. H. DuBell, W. J. Lederer, and T. B. Rogers K+ currents responsible for repolarization in mouse ventricle and their modulation by FK-506 and rapamycin Am J Physiol Heart Circ Physiol, March 1, 2000; 278(3): H886 - H897. [Abstract] [Full Text] [PDF]

				D. G. M. Jugloff, R. Khanna, L. C. Schlichter, and O. T. Jones Internalization of the Kv1.4 Potassium Channel Is Suppressed by Clustering Interactions with PSD-95 J. Biol. Chem., January 14, 2000; 275(2): 1357 - 1364. [Abstract] [Full Text] [PDF]

				A. Epperson, H. P. Bonner, S. M. Ward, W. J. Hatton, K. K. Bradley, M. E. Bradley, J. S. Trimmer, and B. Horowitz Molecular diversity of KV alpha - and beta -subunit expression in canine gastrointestinal smooth muscles Am J Physiol Gastrointest Liver Physiol, July 1, 1999; 277(1): G127 - G136. [Abstract] [Full Text] [PDF]

				D. McKinnon Molecular Identity of Ito : Kv1.4 Redux Circ. Res., March 19, 1999; 84(5): 620 - 622. [Full Text] [PDF]

				J. Zhou, A. Jeron, B. London, X. Han, and G. Koren Characterization of a Slowly Inactivating Outward Current in Adult Mouse Ventricular Myocytes Circ. Res., October 19, 1998; 83(8): 806 - 814. [Abstract] [Full Text] [PDF]

				B. London, W. Guo, X.-h. Pan, J. S. Lee, V. Shusterman, C. J. Rocco, D. A. Logothetis, J. M. Nerbonne, and J. A. Hill Targeted Replacement of Kv1.5 in the Mouse Leads to Loss of the 4-Aminopyridine-Sensitive Component of IK,slow and Resistance to Drug-Induced QT Prolongation Circ. Res., May 11, 2001; 88(9): 940 - 946. [Abstract] [Full Text] [PDF]

				J. M.B. Anumonwo, Y. N. Tallini, F. J. Vetter, and J. Jalife Action Potential Characteristics and Arrhythmogenic Properties of the Cardiac Conduction System of the Murine Heart Circ. Res., August 17, 2001; 89(4): 329 - 335. [Abstract] [Full Text] [PDF]

				V. Trepanier-Boulay, C. St-Michel, A. Tremblay, and C. Fiset Gender-Based Differences in Cardiac Repolarization in Mouse Ventricle Circ. Res., August 31, 2001; 89(5): 437 - 444. [Abstract] [Full Text] [PDF]

				Z. Kassiri, C. Zobel, T.-T. T. Nguyen, J. D. Molkentin, and P. H. Backx Reduction of Ito Causes Hypertrophy in Neonatal Rat Ventricular Myocytes Circ. Res., March 22, 2002; 90(5): 578 - 585. [Abstract] [Full Text] [PDF]