Integration of TRPC6 and NADPH oxidase activation in lysophosphatidylcholine-induced TRPC5 externalization

Lipid oxidation products, including lysophosphatidylcholine (lysoPC), activate canonical transient receptor potential 6 (TRPC6) channels, and the subsequent increase in intracellular Ca leads to TRPC5 activation. The goal of this study is to elucidate the steps in the pathway between TRPC6 activatio...

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Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2017-11, Vol.313 (5), p.C541-C555
Main Authors: Chaudhuri, Pinaki, Rosenbaum, Michael A, Birnbaumer, Lutz, Graham, Linda M
Format: Article
Language:English
Subjects:
Animals
Calcium (intracellular)
Calcium influx
Cattle
Cell Movement - drug effects
Cell Movement - physiology
Cells
Defense mechanisms
Endothelial cells
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Enzyme Activation - physiology
Enzymes
Extracellular signal-regulated kinase
Humans
Intracellular
Kinases
Lipid peroxidation
Lysophosphatidylcholine
Lysophosphatidylcholines - pharmacology
Mice
Mice, Inbred C57BL
Myosin
Myosin-light-chain kinase
NAD(P)H oxidase
NADPH Oxidases - metabolism
Oxidation
Oxygen
Phosphorylation
Reactive oxygen species
Reactive Oxygen Species - metabolism
Ribonucleic acid
RNA
siRNA
Transient receptor potential proteins
TRPC Cation Channels - metabolism
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Summary:Lipid oxidation products, including lysophosphatidylcholine (lysoPC), activate canonical transient receptor potential 6 (TRPC6) channels, and the subsequent increase in intracellular Ca leads to TRPC5 activation. The goal of this study is to elucidate the steps in the pathway between TRPC6 activation and TRPC5 externalization. Following TRPC6 activation by lysoPC, extracellular regulated kinase (ERK) is phosphorylated. This leads to phosphorylation of p47 and subsequent NADPH oxidase activation with increased production of reactive oxygen species. ERK activation requires TRPC6 opening and influx of Ca as evidenced by the failure of lysoPC to induce ERK phosphorylation in TRPC6 endothelial cells. ERK siRNA blocks the lysoPC-induced activation of NADPH oxidase, demonstrating that ERK activation is upstream of NADPH oxidase. The reactive oxygen species produced by NADPH oxidase promote myosin light chain kinase (MLCK) activation with phosphorylation of MLC and TRPC5 externalization. Downregulation of ERK, NADPH oxidase, or MLCK with the relevant siRNA prevents TRPC5 externalization. Blocking MLCK activation prevents the prolonged rise in intracellular calcium levels and preserves endothelial migration in the presence of lysoPC.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00028.2017