hKChIP2 is a functional modifier of hKv4.3 potassium channels: Cloning and expression of a short hKChIP2 splice variant

The Ca(2+) independent transient outward K(+) current (I(to1)) in the heart is responsible for the initial phase of repolarization. The hKv4.3 K(+) channel alpha-subunit contributes to the I(to1) current in many regions of the human heart. Consistently, downregulation of hKv4.3 transcripts in heart...

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Published in:Cardiovascular research 2001-11, Vol.52 (2), p.255-264
Main Authors: DECHER, Niels, UYGUNER, Oya, SCHERER, Constanze R, KARAMAN, Birsen, YÜKSEL-APAK, Memnune, BUSCH, Andreas E, STEINMEYER, Klaus, WOLLNIK, Bernd
Format: Article
Language:English
Subjects:
Alternative Splicing
Animals
Biological and medical sciences
Blotting, Northern - methods
Calcium-Binding Proteins - genetics
Chromosome Mapping
Chromosomes, Human, Pair 10
Cloning, Molecular
Female
Fundamental and applied biological sciences. Psychology
Gene Expression
Gene Transfer Techniques
Heart
Humans
Introns
Kv Channel-Interacting Proteins
Myocardium - chemistry
Myocardium - metabolism
Oocytes - metabolism
Patch-Clamp Techniques
Polymerase Chain Reaction - methods
Potassium Channels - analysis
Potassium Channels - genetics
Potassium Channels, Voltage-Gated
Protein Isoforms - analysis
Protein Isoforms - genetics
Sequence Analysis, DNA
Shal Potassium Channels
Sodium-Potassium-Exchanging ATPase
Vertebrates: cardiovascular system
Xenopus laevis
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Summary:The Ca(2+) independent transient outward K(+) current (I(to1)) in the heart is responsible for the initial phase of repolarization. The hKv4.3 K(+) channel alpha-subunit contributes to the I(to1) current in many regions of the human heart. Consistently, downregulation of hKv4.3 transcripts in heart failure and atrial fibrillation is linked to reduction in I(to1) conductance. The recently cloned KChIP family of calcium sensors has been shown to modulate A-type potassium channels of the Kv4 K(+) channel subfamily. We describe the cloning and tissue distribution of hKChIP2, as well as its functional interaction with hKv4.3 after expression in Xenopus oocytes. Furthermore, we isolated a short splice variant of the hKChIP2 gene (hKCNIP2), which represents the major hKChIP2 transcript. Northern blot analyses revealed that hKChIP2 is expressed in the human heart and occurs in the adult atria and ventricles but not in the fetal heart. Upon coexpression with hKv4.3 both hKChIP2 isoforms increased the current amplitude, slowed the inactivation and increased the recovery from inactivation of hKv4.3 currents. For the first time we analyzed the influence of a KChIP protein on the voltage of half-maximal inactivation of Kv4 channels. We demonstrate that the hKChIP2 isoforms shifted the half-maximal inactivation to more positive potentials, but to a different extent. By elucidating the genomic structure, we provide important information for future analysis of the hKCNIP2 gene in candidate disorders. In the course of this work we mapped the hKCNIP2 gene to chromosome 10q24. Heteromeric hKv4.3/hKChIP2 currents more closely resemble native epicardial I(to1), suggesting that hKChIP2 is a true beta-subunit of human cardiac I(to1). As a result hKChIP2 might play a role in cardiac diseases, where a contribution of I(to1) has been shown.
ISSN:0008-6363
1755-3245
DOI:10.1016/s0008-6363(01)00374-1