Cardiovascular Research Advance Access first published online on February 15, 2008
This version [Corrected Proof] published online on March 13, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn038
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Four and a half LIM protein 1: a partner for KCNA5 in human atrium
1 Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA
2 Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
3 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
4 Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN, USA
5 Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia
* Corresponding author. Tel: +1 615 936 3420; fax: +1 615 343 6334. E-mail address: kathy.murray{at}vanderbilt.edu
Aims: Protein–protein interactions are critical for the normal membrane trafficking, localization, and function of voltage-gated ion channels. In human heart, the Shaker-related voltage-gated K+ channel KCNA5 
-subunit forms the major basis of an atrial-specific, ultra-rapid delayed rectifier K+ current, IKur. We sought to identify proteins that interact with KCNA5 in human atrium and investigate their role in the IKur complex.
Methods and results: Using a glutathione-S-transferase (GST)-KCNA5 C-terminal fusion protein and mass spectrometry-based methods, the scaffolding protein four and a half LIM (for Lin-11, Isl-1, and Mec3) protein 1 (FHL1) was identified as a potential protein partner for KCNA5. Immunoprecipitation experiments confirmed a physical interaction of FHL1 with the K+ channel complex in human atrium, as well as in Chinese hamster ovary (CHO) cells transfected with both KCNA5 and FHL1. In cotransfected cells, confocal microscopy demonstrated areas of colocalization after immunolabelling both proteins. To investigate the functional effects of this interaction, K+ currents were recorded in CHO cells transfected with KCNA5 in the absence and presence of FHL1 coexpression. With coexpression of FHL1, K+ current density was markedly increased, compared with cells expressing KCNA5 alone. This effect was associated with a shift in the voltage dependence of K+ channel activation to more positive potentials, consistent with findings of IKur in atrial myocytes. FHL1 also increased the extent and speed of K+ current slow inactivation, with additional effects on the voltage dependence and recovery of this process.
Conclusion: These results support a role of FHL1 as a key molecular component in the IKur complex in human atrium, where it likely regulates functional expression of KCNA5.
KEYWORDS K+ channel; Ion channels; Membrane currents; Repolarization; Atrial function; FHL1
Time for primary review: 31 days
These authors contributed equally to the manuscript.
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Cardiovasc Res 2008 78: 411-412.
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  D. Dobrev and E. Wettwer Four and a half LIM protein 1: a novel chaperone for atrium-specific Kv1.5 channels with a potential role in atrial arrhythmogenesis Cardiovasc Res, June 1, 2008; 78(3): 411 - 412. [Full Text] [PDF]
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