βiV-Spectrin regulates TREK-1 membrane targeting in the heart

Thomas J. Hund, Jedidiah S. Snyder, Xiangqiong Wu, Patric Glynn, Olha M. Koval, Birce Onal, Nicholas D. Leymaster, Sathya D. Unudurthi, Jerry Curran, Celia Camardo, Patrick J. Wright, Philip F. Binkley, Mark Anderson, Peter J. Mohler

Research output: Contribution to journalArticle

Abstract

AimsCardiac 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 (K2P) family members, despite their potential importance in modulation of heart function.Methods and resultsHere, we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K2P channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e.g. arachidonic acid). We demonstrate that βIV-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 βIV-spectrin lacking TREK-1 binding (qv4J) 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 βIV- spectrin levels in human heart failure.ConclusionsThese data provide new insight into membrane targeting of TREK-1 in the heart and establish a broader role for βIV-spectrin in organizing functional membrane domains critical for normal heart function.

Original languageEnglish (US)
Pages (from-to)166-175
Number of pages10
JournalCardiovascular Research
Volume102
Issue number1
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Spectrin
Membranes
Potassium Channels
Muscle Cells
Voltage-Gated Potassium Channels
potassium channel protein TREK-1
Unsaturated Fatty Acids
Arachidonic Acid
Action Potentials
Actins
Cardiac Arrhythmias
Heart Failure

Keywords

  • Ankyrin
  • Arrhythmia
  • Spectrin
  • TREK-1
  • Two-pore potassium channel

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology
  • Medicine(all)

Cite this

Hund, T. J., Snyder, J. S., Wu, X., Glynn, P., Koval, O. M., Onal, B., ... Mohler, P. J. (2014). βiV-Spectrin regulates TREK-1 membrane targeting in the heart. Cardiovascular Research, 102(1), 166-175. https://doi.org/10.1093/cvr/cvu008

βiV-Spectrin regulates TREK-1 membrane targeting in the heart. / Hund, Thomas J.; Snyder, Jedidiah S.; Wu, Xiangqiong; Glynn, Patric; Koval, Olha M.; Onal, Birce; Leymaster, Nicholas D.; Unudurthi, Sathya D.; Curran, Jerry; Camardo, Celia; Wright, Patrick J.; Binkley, Philip F.; Anderson, Mark; Mohler, Peter J.

In: Cardiovascular Research, Vol. 102, No. 1, 2014, p. 166-175.

Research output: Contribution to journalArticle

Hund, TJ, Snyder, JS, Wu, X, Glynn, P, Koval, OM, Onal, B, Leymaster, ND, Unudurthi, SD, Curran, J, Camardo, C, Wright, PJ, Binkley, PF, Anderson, M & Mohler, PJ 2014, 'βiV-Spectrin regulates TREK-1 membrane targeting in the heart', Cardiovascular Research, vol. 102, no. 1, pp. 166-175. https://doi.org/10.1093/cvr/cvu008
Hund TJ, Snyder JS, Wu X, Glynn P, Koval OM, Onal B et al. βiV-Spectrin regulates TREK-1 membrane targeting in the heart. Cardiovascular Research. 2014;102(1):166-175. https://doi.org/10.1093/cvr/cvu008
Hund, Thomas J. ; Snyder, Jedidiah S. ; Wu, Xiangqiong ; Glynn, Patric ; Koval, Olha M. ; Onal, Birce ; Leymaster, Nicholas D. ; Unudurthi, Sathya D. ; Curran, Jerry ; Camardo, Celia ; Wright, Patrick J. ; Binkley, Philip F. ; Anderson, Mark ; Mohler, Peter J. / βiV-Spectrin regulates TREK-1 membrane targeting in the heart. In: Cardiovascular Research. 2014 ; Vol. 102, No. 1. pp. 166-175.
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abstract = "AimsCardiac 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 (K2P) family members, despite their potential importance in modulation of heart function.Methods and resultsHere, we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K2P channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e.g. arachidonic acid). We demonstrate that βIV-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 βIV-spectrin lacking TREK-1 binding (qv4J) 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 βIV- spectrin levels in human heart failure.ConclusionsThese data provide new insight into membrane targeting of TREK-1 in the heart and establish a broader role for βIV-spectrin in organizing functional membrane domains critical for normal heart function.",
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T1 - βiV-Spectrin regulates TREK-1 membrane targeting in the heart

AU - Hund, Thomas J.

AU - Snyder, Jedidiah S.

AU - Wu, Xiangqiong

AU - Glynn, Patric

AU - Koval, Olha M.

AU - Onal, Birce

AU - Leymaster, Nicholas D.

AU - Unudurthi, Sathya D.

AU - Curran, Jerry

AU - Camardo, Celia

AU - Wright, Patrick J.

AU - Binkley, Philip F.

AU - Anderson, Mark

AU - Mohler, Peter J.

PY - 2014

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N2 - AimsCardiac 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 (K2P) family members, despite their potential importance in modulation of heart function.Methods and resultsHere, we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K2P channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e.g. arachidonic acid). We demonstrate that βIV-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 βIV-spectrin lacking TREK-1 binding (qv4J) 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 βIV- spectrin levels in human heart failure.ConclusionsThese data provide new insight into membrane targeting of TREK-1 in the heart and establish a broader role for βIV-spectrin in organizing functional membrane domains critical for normal heart function.

AB - AimsCardiac 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 (K2P) family members, despite their potential importance in modulation of heart function.Methods and resultsHere, we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K2P channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e.g. arachidonic acid). We demonstrate that βIV-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 βIV-spectrin lacking TREK-1 binding (qv4J) 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 βIV- spectrin levels in human heart failure.ConclusionsThese data provide new insight into membrane targeting of TREK-1 in the heart and establish a broader role for βIV-spectrin in organizing functional membrane domains critical for normal heart function.

KW - Ankyrin

KW - Arrhythmia

KW - Spectrin

KW - TREK-1

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