Modulation of Staurosporine-Activated Volume-Sensitive Outwardly Rectifying Cl- Channel by PI3K/Akt in Cardiomyocytes

Author(s): Yan Liu, Bo Wang, Wei-Wei Zhang, Jia-Ni Liu, Ming-Zhi Shen, Ming-Ge Ding, Xiao-Ming Wang, Jun Ren.

Journal Name: Current Pharmaceutical Design

Volume 19 , Issue 27 , 2013

Abstract:

Chloride (Cl-) channels participate in the regulation of cardiac function in response to stress although the underlying regulatory mechanism remains poorly understood. This study was designed to examine the impact of the pro-apoptotic stimulus staurosporine (STS) on the volume-sensitive outwardly rectifying Cl- current (ICl,Vol) in cardiomyocytes and possible regulatory mechanism involved with a focus on phosphatidylinositol-3 kinase (PI3K)/Akt. Primary cultured rat neonatal cardiomyocytes were subjected to hypotonic and isotonic environment in the presence or absence of STS prior to whole-cell voltage-clamp evaluation of Cl- current. Whole-cell recordings revealed that STS activated an outwardly rectifying Cl- current with phenotypic properties reminiscent of ICl,Vol. These currents were outwardly rectifying with a time-dependent inactivation at positive potentials and were sensitive to 4,4'-diisothiocya-natostilbene- 2,2'- disulfonicacid (DIDS), a non-selective Cl- channel blocker, and 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl)oxybutyric acid (DCPIB), a selective VSOR Cl- channel blocker. DIDS and DCPIB inhibited ICl,Vol by 92.6% ± 7.3% and 78.4% ± 5.5%, respectively. Our data further revealed that the PI3K inhibitor LY294002 facilitated the current with the peak amplitude of 19.54 ± 2.70 pA/pF. To the contrary, insulin partially inhibited the current amplitude with the peak current amplitude of 15.4 ± 2.13 pA/pF. Taken together, our data depicted staurosporine is capable of activating ICl,Vol channel in cardiomyocytes via possibly a PI3K/Akt-dependent mechanism.

Keywords: Volume-sensitive outwardly rectifying Cl- channel, Whole-cell voltage-clamp, Staurosporine, PI3K/Akt.

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Article Details

VOLUME: 19
ISSUE: 27
Year: 2013
Page: [4859 - 4864]
Pages: 6
DOI: 10.2174/1381612811319270008
Price: $58

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