Journal article
beta(IV)-Spectrin regulates TREK-1 membrane targeting in the heart
Cardiovascular research, Vol.102(1), pp.166-175
04/01/2014
DOI: 10.1093/cvr/cvu008
PMCID: PMC3958619
PMID: 24445605
Abstract
Aims Cardiac function depends on the highly regulated and co-ordinate activity of a large ensemble of potassium channels that control myocyte repolarization. While voltage-gated K+ channels have been well characterized in the heart, much less is known about regulation and/or targeting of two-pore K+ channel (K-2P) family members, despite their potential importance in modulation of heart function.
Methods and results Here, we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K-2P channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e. g. arachidonic acid). We demonstrate that beta(IV)-spectrin, an actin-associated protein, is co-localized with TREK-1 at the myocyte intercalated disc, associates with TREK-1 in the heart, and is required for TREK-1 membrane targeting. Mice expressing bIV-spectrin lacking TREK-1 binding (qv(4J)) display aberrant TREK-1 membrane localization, decreased TREK-1 activity, delayed action potential repolarization, and arrhythmia without apparent defects in localization/function of other cardiac potassium channel subunits. Finally, we report abnormal bIV-spectrin levels in human heart failure.
Conclusions These data provide new insight into membrane targeting of TREK-1 in the heart and establish a broader role for beta(IV)-spectrin in organizing functional membrane domains critical for normal heart function.
Details
- Title: Subtitle
- beta(IV)-Spectrin regulates TREK-1 membrane targeting in the heart
- Creators
- Thomas J. Hund - The Ohio State University Wexner Medical CenterJedidiah S. Snyder - The Ohio State UniversityXiangqiong Wu - The Ohio State University Wexner Medical CenterPatric Glynn - The Ohio State UniversityOlha M. Koval - Roy J. and Lucille A. Carver College of MedicineBirce Onal - The Ohio State UniversityNicholas D. Leymaster - Roy J. and Lucille A. Carver College of MedicineSathya D. Unudurthi - The Ohio State University Wexner Medical CenterJerry Curran - The Ohio State University Wexner Medical CenterCelia Camardo - The Ohio State University Wexner Medical CenterPatrick J. Wright - The Ohio State University Wexner Medical CenterPhilip F. Binkley - The Ohio State University Wexner Medical CenterMark E. Anderson - University of IowaPeter J. Mohler - The Ohio State University Wexner Medical Center
- Resource Type
- Journal article
- Publication Details
- Cardiovascular research, Vol.102(1), pp.166-175
- Publisher
- Oxford Univ Press
- DOI
- 10.1093/cvr/cvu008
- PMID
- 24445605
- PMCID
- PMC3958619
- ISSN
- 0008-6363
- eISSN
- 1755-3245
- Number of pages
- 10
- Grant note
- James S. McDonnell Foundation Saving Tiny Hearts Society Fondation Leducq Transatlantic Alliance for CaMKII Signaling American Heart Association HL 096805; HL114893; HL084583; HL083422; HL114383; HL079031; HL096652; HL113001; HL070250 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL114383 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Language
- English
- Date published
- 04/01/2014
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984359833502771
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