Abstract
Large conductance Ca2+-activated potassium channels (BK) are targets for research that explores therapeutic means to various diseases, owing to the roles of the channels in mediating multiple physiological processes in various cells and tissues. We investigated the pharmacological effects of curcumin, a compound isolated from the herb Curcuma longa, on BK channels. As recorded by whole-cell patch-clamp, curcumin increased BK (α) and BK (α+β1) currents in transfected HEK293 cells as well as the current density of BK in A7r5 smooth muscle cells in a dose-dependent manner. By incubating with curcumin for 24 hours, the current density of exogenous BK (α) in HEK293 cells and the endogenous BK in A7r5 cells were both enhanced notably, though the steady-state activation of the channels did not shift significantly, except for BK (α+β1). Curcumin up-regulated the BK protein expression without changing its mRNA level in A7r5 cells. The surface expression and the half-life of BK channels were also increased by curcumin in HEK293 cells. These effects of curcumin were abolished by MG-132, a proteasome inhibitor. Curcumin also increased ERK 1/2 phosphorylation, while inhibiting ERK by U0126 attenuated the curcumin-induced up-regulation of BK protein expression. We also observed that the curcumin-induced relaxation in the isolated rat aortic rings was significantly attenuated by paxilline, a BK channel specific blocker. These results show that curcumin enhances the activity of the BK channels by interacting with BK directly as well as enhancing BK protein expression through inhibiting proteasomal degradation and activating ERK signaling pathway. The findings suggest that curcumin is a potential BK channel activator and provide novel insight into its complicated pharmacological effects and the underlying mechanisms.
Highlights
Large conductance Ca2+-activated potassium (BK) channels, composed of α and tissue-specific β subunits, are present in a wide variety of cell types and are especially abundant in some of the excitable cells such as smooth muscle cells, neurons, and endocrine cells [1]
To investigate the effect of curcumin on BK channel activity, outward potassium currents were measured in HEK293 cells transiently overexpressing BK channel
The effects of curcumin on the voltage dependent activation of the BK channel expressed in HEK293 cells were analyzed as described in Data analysis
Summary
Large conductance Ca2+-activated potassium (BK) channels, composed of α and tissue-specific β subunits, are present in a wide variety of cell types and are especially abundant in some of the excitable cells such as smooth muscle cells, neurons, and endocrine cells [1]. Up-Regulatory Effects of Curcumin on BK Channels www.wsjsw.gov.cn/wsj/): preparation of the manuscript, Innovation Program of Shanghai Municipal Education Commission (NO.15ZZ063) Tao) (http://www.shmec.gov.cn/): preparation of the manuscript and Research Project of Putuo Hospital, Shanghai University of Traditional Chinese Medicine (NO.2014YJ002) Tao) (http://www.sptdch.cn/): data collection and analysis and preparation of the manuscript
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