Four Kinetically Distinct Depolarization-activated K+ Currents in Adult Mouse Ventricular Myocytes

In the experiments here, the time- and voltage-dependent properties of the Ca2+-independent, depolarization-activated K+ currents in adult mouse ventricular myocytes were characterized in detail. In the majority (65 of 72, ≈ 90%) of cells dispersed from the ventricles, analysis of the decay phases of the outward currents revealed three distinct K+ current components: a rapidly inactivating, transient outward K+ current, Ito,f (mean ± SEM τdecay = 85 ± 2 ms); a slowly (mean ± SEM τdecay = 1,162 ± 29 ms) inactivating K+ current, IK,slow; and a non inactivating, steady state current, Iss. In a small subset (7 of 72, ≈ 10%) of cells, Ito,f was absent and a slowly inactivating (mean ± SEM τdecay = 196 ± 7 ms) transient outward current, referred to as Ito,s, was identified; the densities and properties of IK,slow and Iss in Ito,s-expressing cells are indistinguishable from the corresponding currents in cells with Ito,f. Microdissection techniques were used to remove tissue pieces from the left ventricular apex and from the ventricular septum to allow the hypothesis that there are regional differences in Ito,f and Ito,s expression to be tested directly. Electrophysiological recordings revealed that all cells isolated from the apex express Ito,f (n = 35); Ito,s is not detected in these cells (n = 35). In the septum, by contrast, all of the cells express Ito,s (n = 28) and in the majority (22 of 28, 80%) of cells, Ito,f is also present. The density of Ito,f (mean ± SEM at +40 mV = 6.8 ± 0.5 pA/pF, n = 22) in septum cells, however, is significantly (P < 0.001) lower than Ito,f density in cells from the apex (mean ± SEM at +40 mV = 34.6 ± 2.6 pA/pF, n = 35). In addition to differences in inactivation kinetics, Ito,f, Ito,s, and IK,slow display distinct rates of recovery (from inactivation), as well as differential sensitivities to 4-aminopyridine (4-AP), tetraethylammonium (TEA), and Heteropoda toxin-3. IK,slow, for example, is blocked selectively by low (10–50 μM) concentrations of 4-AP and by (≥25 mM) TEA. Although both Ito,f and Ito,s are blocked by high (>100 μM) 4-AP concentrations and are relatively insensitive to TEA, Ito,f is selectively blocked by nanomolar concentrations of Heteropoda toxin-3, and Ito,s (as well as IK,slow and Iss) is unaffected. Iss is partially blocked by high concentrations of 4-AP or TEA. The functional implications of the distinct properties and expression patterns of Ito,f and Ito,s, as well as the likely molecular correlates of these (and the IK,slow and Iss) currents, are discussed.

[1]  Properties of an early outward current in single cells of the mouse ventricle. , 1988, General physiology and biophysics.

[2]  G. Lyons,et al.  Developmental regulation of myosin gene expression in mouse cardiac muscle , 1990, The Journal of cell biology.

[3]  M. Tanouye,et al.  Molecular cloning and functional expression of a potassium channel cDNA isolated from a rat cardiac library , 1990, FEBS letters.

[4]  I. Grupp,et al.  Cardiac myosin heavy chain mRNA expression and myocardial function in the mouse heart. , 1991, Circulation research.

[5]  P. Kuo,et al.  Cardiac Electrophysiology: From Cell to Bedside , 1991 .

[6]  R. Kass,et al.  Potassium Channels in the Heart: Electrophysiology and Pharmacological Regulation , 1991 .

[7]  Francisco Bezanilla,et al.  Gating currents from a nonconducting mutant reveal open-closed conformations in Shaker K+ channels , 1993, Neuron.

[8]  E Erdmann,et al.  Characteristics of transient outward current in human ventricular myocytes from patients with terminal heart failure. , 1993, Circulation research.

[9]  H. Strauss,et al.  Cloning and characterization of an Ito-like potassium channel from ferret ventricle. , 1994, The American journal of physiology.

[10]  D. Mckinnon,et al.  Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats. , 1994, Circulation research.

[11]  P. Boyden,et al.  Ion channel function in disease. , 1995, Cardiovascular research.

[12]  J. Nerbonne,et al.  Differential expression of voltage-gated K+ channel subunits in adult rat heart. Relation to functional K+ channels? , 1995, Circulation Research.

[13]  J. Nerbonne,et al.  Developmental analysis reveals mismatches in the expression of K+ channel alpha subunits and voltage-gated K+ channel currents in rat ventricular myocytes , 1996, The Journal of general physiology.

[14]  S. Ebashi,et al.  Molecular Physiology and Pharmacology of Cardiac Ion Channels and Transporters , 1996, Developments in Cardiovascular Medicine.

[15]  J. Fewell,et al.  Transgenic remodeling of the contractile apparatus in the mammalian heart. , 1996, Circulation research.

[16]  W. Giles,et al.  Ca2+-independent transient outward current in mammalian heart , 1996 .

[17]  D. Mckinnon,et al.  Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current. , 1996, Circulation research.

[18]  A. Ribera Homogeneous development of electrical excitability via heterogeneous ion channel expression , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[19]  M. Tamkun,et al.  Molecular physiology of cardiac potassium channels. , 1996, Physiological reviews.

[20]  J. Nerbonne,et al.  Myocardial potassium channels: electrophysiological and molecular diversity. , 1996, Annual review of physiology.

[21]  W. Giles,et al.  Shal‐type channels contribute to the Ca2+‐independent transient outward K+ current in rat ventricle. , 1997, The Journal of physiology.

[22]  Y. Mori,et al.  A Cellular Model for Long QT Syndrome , 1997, The Journal of Biological Chemistry.

[23]  A. Wilde,et al.  Ion Channels, the QT Interval, and Arrhythmias , 1997, Pacing and clinical electrophysiology : PACE.

[24]  M. Jiang,et al.  Suppression of Slow Delayed Rectifier Current by a Truncated Isoform of KvLQT1 Cloned from Normal Human Heart* , 1997, The Journal of Biological Chemistry.

[25]  H. Duff,et al.  Developmental changes in transient outward current in mouse ventricle. , 1997, Circulation research.

[26]  W. Giles,et al.  A rapidly activating sustained K+ current modulates repolarization and excitation–contraction coupling in adult mouse ventricle , 1997, The Journal of physiology.

[27]  J. Nerbonne,et al.  Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation. , 1997, Circulation research.

[28]  R. Grange,et al.  Pleiotropic effects of a disrupted K+ channel gene: reduced body weight, impaired motor skill and muscle contraction, but no seizures. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[29]  E. Marbán,et al.  Suppression of Neuronal and Cardiac Transient Outward Currents by Viral Gene Transfer of Dominant-Negative Kv4.2 Constructs* , 1997, The Journal of Biological Chemistry.

[30]  Harry Hines Boulevard Pleiotropic effects of a disrupted K 1 channel gene: Reduced body weight, impaired motor skill and muscle contraction, but no seizures , 1997 .

[31]  Dao-wu Wang,et al.  The transient outward current in mice lacking the potassium channel gene Kv1.4 , 1998, The Journal of physiology.

[32]  Hao Wang,et al.  Deletion of the KV1.1 Potassium Channel Causes Epilepsy in Mice , 1998, Neuron.

[33]  J. Nerbonne,et al.  Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunit. , 1998, Circulation research.

[34]  M. Näbauer,et al.  Potassium channel down-regulation in heart failure. , 1998, Cardiovascular research.

[35]  J. Nerbonne Regulation of voltage-gated K+ channel expression in the developing mammalian myocardium. , 1998, Journal of neurobiology.

[36]  G. Mitchell,et al.  Long QT and ventricular arrhythmias in transgenic mice expressing the N terminus and first transmembrane segment of a voltage-gated potassium channel. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[37]  B. London,et al.  Characterization of a slowly inactivating outward current in adult mouse ventricular myocytes. , 1998, Circulation research.

[38]  J. Nerbonne,et al.  Expression environment determines K+ current properties: Kv1 and Kv4 α-subunit-induced K+ currents in mammalian cell lines and cardiac myocytes , 1999, Pflügers Archiv.

[39]  J. Nerbonne,et al.  Distinct Transient Outward Potassium Current (Ito) Phenotypes and Distribution of Fast-inactivating Potassium Channel Alpha Subunits in Ferret Left Ventricular Myocytes , 1999, The Journal of general physiology.