Modulation of cardiac mechanosensitive ion channels involves superoxide, nitric oxide and peroxynitrite.
In murine ventricular myocytes, activation of mechanosensitive ion channels (MSCs) includes activation of non-selective cation currents and deactivation of inwardly rectifying potassium currents. Using pharmacological inhibitors and knockout models, we analyzed signaling steps that are critical to transduce the mechanical signal (stretch) into electrophysiological events (MSC). We provide evidence for an activation of NAD(P)H oxidase and NOS3 in response to stretch putatively via the angiotensin II receptor type 1. The involvement of superoxide and nitric oxide was verified by the block of MSC using specific scavengers (tiron and PTIO, respectively). Superoxide and nitric oxide are known to combine very rapidly to form peroxynitrite. Accordingly, MSC were blocked by the peroxynitrite scavenger uric acid and could be mimicked by application of exogenous peroxynitrite. Peroxynitrite formation may activate phospholipases generating amphipaths that modulates channel function via changing the curvature of the surrounding lipid bilayer. This conclusion is supported by our findings that MSC were suppressed by inhibitors of phospholipases but could be mimicked by exogenous phospholipases or by amphipaths (oleic acid, Triton X-100).
Dyachenko
V
V
Department of Physiology, Martin-Luther-University, Halle, Germany.
Rueckschloss
U
U
Isenberg
G
G
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D040542:Mechanotransduction, Cellular / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology*; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000737:chemistry / Q000378:metabolism*; D010740:Phospholipases / Q000378:metabolism; D015221:Potassium Channels / Q000502:physiology*; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D003497:Cyclic N-Oxides; D007093:Imidazoles; D015221:Potassium Channels; D013481:Superoxides; D030421:Peroxynitrous Acid; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019255:NADPH Oxidases; D010740:Phospholipases