The interaction of caveolin 3 protein with the potassium inward rectifier channel Kir2.1: Physiology and pathology related to long QT syndrome 9 (LQT9)

Ravi Vaidyanathan, Amanda L. Vega, Chunhua Song, Qing Zhou, Bihua Tan, Stuart Berger, Jonathan C. Makielski, Lee L. Eckhardt

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Mutations in CAV3 cause LQT syndrome 9 (LQT9). A previously reported LQT9 patient had prominent U waves on ECG, a feature that has been correlated with Kir2.1 loss of function. Our objective was to determine whether caveolin 3 (Cav3) associates with Kir2.1 and whether LQT9-associated CAV3 mutations affect the biophysical properties of Kir2.1. Kir2.1 current (IK1) density was measured using the whole-cell voltage clamp technique. WT-Cav3 did not affect IK1. However, F97C-Cav3 and T78M-Cav3 decreased IK1 density significantly by ∼60%, and P104L-Cav3 decreased IK1 density significantly by ∼30% at -60 mV. Immunostained rat heart cryosections and HEK293 cells cotransfected with Kir2.1 and WT-Cav3 both demonstrated colocalization of Kir2.1 and WT-Cav3 by confocal imaging. Cav3 coimmunoprecipitated with Kir2.1 in human ventricular myocytes and in heterologous expression systems. Additionally, FRET efficiency was highly specific, with a molecular distance of 5.6 ± 0.4 nm, indicating close protein location. Colocalization experiments found that Cav3 and Kir2.1 accumulated in the Golgi compartment. On-cell Western blot analysis showed decreased Kir2.1 cell surface expression by 60% when expressed with F97C-Cav3 and by 20% when expressed with P104L-Cav3 compared with WT-Cav3. This is the first report of an association between Cav3 and Kir2.1. The Cav3 mutations F97C-Cav3, P104L-Cav3, and T78M-Cav3 decreased IK1 density significantly. This effect was related to a reduced cell surface expression of Kir2.1. Kir2.1 loss of function is additive to the increase described previously in late INa, prolonging repolarization and leading to arrhythmia generation in Cav3-mediated LQT9.

Original languageEnglish (US)
Pages (from-to)17472-17480
Number of pages9
JournalJournal of Biological Chemistry
Volume288
Issue number24
DOIs
StatePublished - Jun 14 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'The interaction of caveolin 3 protein with the potassium inward rectifier channel Kir2.1: Physiology and pathology related to long QT syndrome 9 (LQT9)'. Together they form a unique fingerprint.

Cite this