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


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.
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, 473 W. 12th Avenue, 43210 Columbus, OH, USA.
Thomas J
TJ
Hund
Jedidiah S
JS
Snyder
Xiangqiong
X
Wu
Patric
P
Glynn
Olha M
OM
Koval
Birce
B
Onal
Nicholas D
ND
Leymaster
Sathya D
SD
Unudurthi
Jerry
J
Curran
Celia
C
Camardo
Patrick J
PJ
Wright
Philip F
PF
Binkley
Mark E
ME
Anderson
Peter J
PJ
Mohler
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism*; D013049:Spectrin / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C417303:betaIV spectrin; C103742:potassium channel protein TREK-1; D013049:Spectrin
Ankyrin; Arrhythmia; Spectrin; TREK-1; Two-pore potassium channel