title: Lipid peroxidation is essential for phospholipase C activity and the inositol-trisphosphate-related Ca²⁺ signal.
abstract: Reactive oxygen species (ROS) are produced in enzymatic and non-enzymatic reactions and have important roles in cell signalling but also detrimental effects. ROS-induced damage has been implicated in a number of neurological diseases; however, antioxidant therapies targeting brain diseases have been unsuccessful. Such failure might be related to inhibition of ROS-induced signalling in the brain. Using direct kinetic measures of lipid peroxidation in astrocytes and measurements of lipid peroxidation products in brain tissue, we here show that phospholipase C (PLC) preferentially cleaves oxidised lipids. Because of this, an increase in the rate of lipid peroxidation leads to increased Ca(2+) release from endoplasmic reticulum (ER) stores in response to physiological activation of purinoreceptors with ATP. Both vitamin E and its water-soluble analogue Trolox, potent ROS scavengers, were able to suppress PLC activity, therefore dampening intracellular Ca(2+) signalling. This implies that antioxidants can compromise intracellular Ca(2+) signalling through inhibition of PLC, and that PLC plays a dual role - signalling and antioxidant defence.
authors.affiliation: UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Ana-Marija
authors.initials: AM
authors.lastname: Domijan
authors.forename: Stjepana
authors.initials: S
authors.lastname: Kovac
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D018920:Coculture Techniques; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D015227:Lipid Peroxidation; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D011983:Receptors, Purinergic; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002839:Chromans; D017382:Reactive Oxygen Species; D011983:Receptors, Purinergic; D014810:Vitamin E; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D010738:Type C Phospholipases; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D002118:Calcium
keywords: Astrocyte; Ca2+; Lipid peroxidation; Phospholipase C