?(IV)-Spectrin regulates TREK-1 membrane targeting in the heart.
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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 ?(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 ?(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 ?(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 ?(IV)-spectrin in organizing functional membrane domains critical for normal heart function.
SUBMITTER: Hund TJ
PROVIDER: S-EPMC3958619 | biostudies-literature |
REPOSITORIES: biostudies-literature
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2022-02-17 | PXD025776 | Pride