β(IV)-Spectrin regulates TREK-1 membrane targeting in the heart.

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 β(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 β(IV)-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 β(IV)-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 β(IV)-spectrin in organizing functional membrane domains critical for normal heart function.

• Authors: 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 E Anderson, Peter J Mohler
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 102 Issue 1 Pg. 166-75 (Apr 01 2014) ISSN: 1755-3245 [Electronic] England
• PMID: 24445605 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Tissue Proteins
• Potassium Channels, Tandem Pore Domain
• betaIV spectrin
• potassium channel protein TREK-1
• Spectrin

Topics

• Animals
• Cell Membrane (metabolism)
• Mice
• Myocardium (cytology, metabolism)
• Nerve Tissue Proteins (metabolism)
• Potassium Channels, Tandem Pore Domain (metabolism)
• Spectrin (metabolism)