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

Cardiovascular research | Apr 1, 2014

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.

Pubmed ID: 24445605 RIS Download

Mesh terms: Animals | Cell Membrane | Mice | Myocardium | Nerve Tissue Proteins | Potassium Channels, Tandem Pore Domain | Spectrin

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Associated grants

  • Agency: NHLBI NIH HHS, Id: HL084583
  • Agency: NHLBI NIH HHS, Id: R01 HL079031
  • Agency: NHLBI NIH HHS, Id: R01 HL096652
  • Agency: NHLBI NIH HHS, Id: R01 HL083422
  • Agency: NHLBI NIH HHS, Id: HL083422
  • Agency: NHLBI NIH HHS, Id: HL079031
  • Agency: NHLBI NIH HHS, Id: R01 HL084583
  • Agency: NHLBI NIH HHS, Id: R01 HL070250
  • Agency: NHLBI NIH HHS, Id: R00 HL096805
  • Agency: NHLBI NIH HHS, Id: HL 096805
  • Agency: NHLBI NIH HHS, Id: HL070250
  • Agency: NHLBI NIH HHS, Id: HL096652
  • Agency: NHLBI NIH HHS, Id: HL114893
  • Agency: NHLBI NIH HHS, Id: HL113001
  • Agency: NHLBI NIH HHS, Id: HL114383
  • Agency: NHLBI NIH HHS, Id: R01 HL114893

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