Suppression of Slow Delayed Rectifier Current by a Truncated Isoform of KvLQT1 Cloned from Normal Human Heart*

It has been suggested that the cardiac slow delayed rectifier channel is formed by the association of two subunits: IsK (also called minK) and KvLQT1. N-terminal splice variants of the human KvLQT1 gene have been identified, but the functional roles of different KvLQT1 isoforms are not clear. Using the nested 5′-rapid amplification of cDNA ends technique, we obtained a truncated isoform of KvLQT1 (termed tKvLQT1) that lacks the N-terminal cytoplasmic domain and the initial one-third of the first transmembrane domain. The function of tKvLQT1 was tested by oocyte expression, alone or together with the full-length KvLQT1 or a human IsK clone (hIsK). tKvLQT1 alone did not generate functional channels. However, it suppressed the KvLQT1 current when coexpressed with the full-length isoform. It also suppressed the slow delayed rectifier current induced by hIsK, probably by competing with the KvLQT1 subunit endogenous toXenopus oocytes in coassembly with the hIsK subunit. On the other hand, tKvLQT1 did not suppress the expression of Kv1.4, Kv4.3, or hERG. Using the reverse transcription-polymerase chain reaction technique, we further show that the truncated and full-length isoforms are coexpressed in different regions of human heart. Therefore, tKvLQT1 may modulate the function of IKs in human cardiac myocytes.

[1]  M. Blanar,et al.  KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Y. Yazaki,et al.  Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome. , 1997, Circulation.

[3]  P. Coumel,et al.  A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome , 1997, Nature Genetics.

[4]  A. Feinberg,et al.  Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements , 1997, Nature Genetics.

[5]  M. Sanguinetti,et al.  Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKS potassium channel , 1996, Nature.

[6]  Jacques Barhanin,et al.  KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium current , 1996, Nature.

[7]  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.

[8]  F. Collins,et al.  KVLQT1 mutations in three families with familial or sporadic long QT syndrome. , 1996, Human molecular genetics.

[9]  B. Rudy,et al.  Cloning of a novel component of A-type K+ channels operating at subthreshold potentials with unique expression in heart and brain. , 1996, Journal of neurophysiology.

[10]  G. Landes,et al.  Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias , 1996, Nature Genetics.

[11]  G. Robertson,et al.  HERG, a human inward rectifier in the voltage-gated potassium channel family. , 1995, Science.

[12]  M. Sanguinetti,et al.  A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel , 1995, Cell.

[13]  C. Antzelevitch,et al.  Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. , 1995, Circulation research.

[14]  H. Lester,et al.  Beta-adrenergic modulation of currents produced by rat cardiac Na+ channels expressed in Xenopus laevis oocytes. , 1994, Receptors & channels.

[15]  Functional role of the NH2-terminal cytoplasmic domain of a mammalian A- type K channel , 1993, The Journal of general physiology.

[16]  C Antzelevitch,et al.  Drug‐Induced Afterdepolarizations and Triggered Activity Occur in a Discrete Subpopulation of Ventricular Muscle Cells (M Cells) in the Canine Heart: , 1993, Journal of cardiovascular electrophysiology.

[17]  Y. Jan,et al.  Specification of subunit assembly by the hydrophilic amino-terminal domain of the Shaker potassium channel. , 1992, Science.

[18]  R. MacKinnon Determination of the subunit stoichiometry of a voltage-activated potassium channel , 1991, Nature.

[19]  R. Stein,et al.  Cloning and expression of the delayed-rectifier IsK channel from neonatal rat heart and diethylstilbestrol-primed rat uterus. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[20]  S. Nakanishi,et al.  Cloning of a membrane protein that induces a slow voltage-gated potassium current. , 1988, Science.