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Inhibition of endothelial cell Ca 2+ entry and transient receptor potential channels by S igma‐1 receptor ligands
Author(s) -
Amer Mohamed S,
McKeown Lynn,
Tumova Sarka,
Liu Ruifeng,
Seymour Victoria AL,
Wilson Lesley A,
Naylor Jacqueline,
Greenhalgh Katriona,
Hou Bing,
Majeed Yasser,
Turner Paul,
Sedo Alicia,
O'Regan David J,
Li Jing,
Bon Robin S,
Porter Karen E,
Beech David J
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12041
Subject(s) - transient receptor potential channel , trpc , agonist , chemistry , microbiology and biotechnology , receptor , trpc5 , calcium in biology , voltage dependent calcium channel , inhibitory postsynaptic potential , pharmacology , calcium , biochemistry , biology , endocrinology , organic chemistry
Background and Purpose The S igma‐1 receptor ( Sig1R ) impacts on calcium ion signalling and has a plethora of ligands. This study investigated Sig1R and its ligands in relation to endogenous calcium events of endothelial cells and transient receptor potential ( TRP ) channels. Experimental Approach Intracellular calcium and patch clamp measurements were made from human saphenous vein endothelial cells and HEK 293 cells expressing exogenous human TRPC 5, TRPM 2 or TRPM 3. Sig1R ligands were applied and short interfering RNA was used to deplete Sig1R . TRP channels tagged with fluorescent proteins were used for subcellular localization studies. Key Results In endothelial cells, 10–100 μ M of the Sig1R antagonist BD 1063 inhibited sustained but not transient calcium responses evoked by histamine. The Sig1R agonist 4‐ IBP and related antagonist BD 1047 were also inhibitory. The Sig1R agonist SKF 10047 had no effect. Sustained calcium entry evoked by VEGF or hydrogen peroxide was also inhibited by BD 1063, BD 1047 or 4‐ IBP , but not SKF 10047. 4‐ IBP , BD 1047 and BD 1063 inhibited TRPC 5 or TRPM 3, but not TRPM 2. Inhibitory effects of BD 1047 were rapid in onset and readily reversed on washout. SKF 10047 inhibited TRPC 5 but not TRPM 3 or TRPM 2. Depletion of Sig1R did not prevent the inhibitory actions of BD 1063 or BD 1047 and Sig1R did not co‐localize with TRPC 5 or TRPM 3. Conclusions and Implications The data suggest that two types of Sig1R ligand ( BD 1047/ BD 1063 and 4‐ IBP ) are inhibitors of receptor‐ or chemically activated calcium entry channels, acting relatively directly and independently of the Sig1R . Chemical foundations for TRP channel inhibitors are suggested.