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Mechanism of loss of Kv11.1 K+ current in mutant T421M-Kv11.1-expressing rat ventricular myocytes: interaction of trafficking and gating. Circulation 2012 Dec 11;126(24):2809-18



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Scopus ID

2-s2.0-84870910786   11 Citations


BACKGROUND: Type 2 long QT syndrome involves mutations in the human ether a-go-go-related gene (hERG or KCNH2). T421M, an S1 domain mutation in the Kv11.1 channel protein, was identified in a resuscitated patient. We assessed its biophysical, protein trafficking, and pharmacological mechanisms in adult rat ventricular myocytes.

METHODS AND RESULTS: Isolated adult rat ventricular myocytes were infected with wild-type (WT)-Kv11.1- and T421M-Kv11.1-expressing adenovirus and analyzed with the use of patch clamp, Western blot, and confocal imaging techniques. Expression of WT-Kv11.1 or T421M-Kv11.1 produced peak tail current (I(Kv11.1)) of 8.78A?1.18 and 1.91A?0.22 pA/pF, respectively. Loss of mutant I(Kv11.1) resulted from (1) a partially trafficking-deficient channel protein with reduced cell surface expression and (2) altered channel gating with a positive shift in the voltage dependence of activation and altered kinetics of activation and deactivation. Coexpression of WT+T421M-Kv11.1 resulted in heterotetrameric channels that remained partially trafficking deficient with only a minimal increase in peak I(Kv11.1) density, whereas the voltage dependence of channel gating became WT-like. In the adult rat ventricular myocyte model, both WT-Kv11.1 and T421M-Kv11.1 channels responded to I?-adrenergic stimulation by increasing I(Kv11.1).

CONCLUSIONS: The T421M-Kv11.1 mutation caused a loss of I(Kv11.1) through interactions of abnormal protein trafficking and channel gating. Furthermore, for coexpressed WT+T421M-Kv11.1 channels, different dominant-negative interactions govern protein trafficking and ion channel gating, and these are likely to be reflected in the clinical phenotype. Our results also show that WT and mutant Kv11.1 channels responded to I?-adrenergic stimulation.

Author List

Balijepalli SY, Lim E, Concannon SP, Chew CL, Holzem KE, Tester DJ, Ackerman MJ, Delisle BP, Balijepalli RC, January CT


Kassandra E. Holzem MD Assistant Professor in the Dermatology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
HEK293 Cells
Ion Channel Gating
Long QT Syndrome
Membrane Potentials
Mutation, Missense
Myocytes, Cardiac
Patch-Clamp Techniques
Protein Transport
Rats, Sprague-Dawley
Receptors, Adrenergic, beta