title: TASK-1 channels in oligodendrocytes: a role in ischemia mediated disruption.
abstract: Oligodendrocytes are the myelinating cells of the CNS and, like neurons, are highly sensitive to ischemic damage. However, the mechanisms underlying cytotoxicity in oligodendrocytes during hypoxic/ischemic episodes are not fully understood. TASK-1 is a K(+) leak channel that mediates hypoxic depolarisation in neurons. The expression and function of TASK-1 in oligodendrocytes had not previously been addressed. In this study, we investigate the expression of TASK-1 in oligodendrocytes and its role in white matter ischemic damage. Expression of TASK-1 in oligodendrocytes was investigated in the mouse brain using immunostaining. TASK-1 channel function was identified by established pharmacological and electrophysiological strategies, using the whole-cell patch clamp technique in cell cultures of oligodendrocytes from the optic nerve, a typical white matter tract. The role of TASK-1 in hypoxia was examined in isolated intact optic nerves subjected to oxygen glucose deprivation (OGD). Oligodendrocytes are strongly immunopositive for TASK-1 throughout the brain. Patch-clamp identified functional TASK-1-like leak currents in oligodendrocytes using two recognised means of inhibiting TASK-1, decreasing extracellular pH to 6.4 and exposure to the TASK-1 selective inhibitor anandamide. Incubation of optic nerves with methanandamide, a non-hydrolysable form of anandamide, significantly protected oligodendrocytes against hypoxic disruption and death in OGD. Our data demonstrate for the first time that oligodendrocytes express functional TASK-1 channels and provide compelling evidence they contribute to oligodendrocyte damage in hypoxia. Since oligodendrocyte damage is a key factor in ischemic episodes, TASK-1 may provide a potential therapeutic target in stroke and white matter disease.
authors.affiliation: Institute of Biomedical and Biomolecular Science, University of Portsmouth, St Michael's Building, White Swan Rd, Portsmouth, UK.
authors.forename: Virginia
authors.initials: V
authors.lastname: Hawkins
authors.forename: Arthur
authors.initials: A
authors.lastname: Butt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000494:pharmacology; D055592:Biophysical Phenomena / Q000502:physiology; D001921:Brain / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004558:Electric Stimulation; D063388:Endocannabinoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000473:pathology; D007511:Ischemia; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism*; D009900:Optic Nerve / Q000166:cytology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011522:Protons
chemical_list: D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063388:Endocannabinoids; D008164:Luminescent Proteins; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; C047516:Plp1 protein, mouse; D053284:Polyunsaturated Alkamides; D024683:Potassium Channels, Tandem Pore Domain; D011522:Protons; C413663:fluorescent protein 583; C420132:potassium channel subfamily K member 3; D005947:Glucose; C078814:anandamide