title: Up-Regulatory Effects of Curcumin on Large Conductance Ca2+-Activated K+ Channels.
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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China.
authors.forename: Qijing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China.|Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine,164 Lanxi road, Shanghai, 200062, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China.
authors.forename: Hongya
authors.initials: H
authors.lastname: Hei
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China.
authors.forename: Fangping
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine,164 Lanxi road, Shanghai, 200062, China.
authors.forename: Yunman
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine,164 Lanxi road, Shanghai, 200062, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Peng
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D003474:Curcumin; D057809:HEK293 Cells; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D007976:Leupeptins / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D002070:Butadienes; D051036:Large-Conductance Calcium-Activated Potassium Channels; D007976:Leupeptins; D009570:Nitriles; C113580:U 0126; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde