Journal
SCIENCE SIGNALING
Volume 8, Issue 358, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2005659
Keywords
-
Categories
Funding
- NIH [HL091905, F31HL094145, HL067061, HL110347, HL094378]
- American Heart Association Postdoctoral Fellowship
- American Heart Association Scientist Development Grant [11SDG7360050]
- Canadian Institute of Health Research
- Monfort Family Foundation
Ask authors/readers for more resources
Reactive oxygen species (ROS) can have divergent effects in cerebral and peripheral circulations. We found that Ca2+-permeable transient receptor potential ankyrin 1 (TRPA1) channels were present and co-localized with NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 2 (NOX2), a major source of ROS, in the endothelium of cerebral arteries but not in other vascular beds. We recorded and characterized ROS-triggered Ca2+ signals representing Ca2+ influx through single TRPA1 channels, which we called TRPA1 sparklets. TRPA1 sparklet activity was low under basal conditions but was stimulated by NOX-generated ROS. Ca2+ entry during a single TRPA1 sparklet was twice that of a TRPV4 sparklet and similar to 200 times that of an L-type Ca2+ channel sparklet. TRPA1 sparklets representing the simultaneous opening of two TRPA1 channels were more common in endothelial cells than in human embryonic kidney (HEK) 293 cells expressing TRPA1. The NOX-induced TRPA1 sparklets activated intermediate-conductance, Ca2+-sensitive K+ channels, resulting in smooth muscle hyperpolarization and vasodilation. NOX-induced activation of TRPA1 sparklets and vasodilation required generation of hydrogen peroxide and lipid-peroxidizing hydroxyl radicals as intermediates. 4-Hydroxy-nonenal, a metabolite of lipid peroxidation, also increased TRPA1 sparklet frequency and dilated cerebral arteries. These data suggest that in the cerebral circulation, lipid peroxidation metabolites generated by ROS activate Ca2+ influx through TRPA1 channels in the endothelium of cerebral arteries to cause dilation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available