ATP release by way of connexin 36 hemichannels mediates ischemic tolerance in vitro.
Spreading depression (SD) is a self-propagating wave of neuronal and glial depolarization that may occur in virtually any gray matter region in the brain. One consequence of SD is an increased tolerance to ischemia. It has been shown that during cortical SD ATP is released into the extracellular space and activation of purinergic receptors leads to the induction of ischemic tolerance. In the present study we show that depolarization of cultured neurons induces ischemic tolerance which is mediated by purinergic receptor activation. Depolarization causes the release of ATP into the extracellular medium, which may be prevented by treatment with the connexin hemichannel blockers flufenamic acid and quinine, but not the pannexin hemichannel blocker carbenoxolone. Knockdown of connexin 36 expression by siRNA greatly reduces the amount of ATP released during depolarization and the subsequent degree of ischemic tolerance. We conclude that during depolarization neurons release ATP by way of connexin 36 hemichannels.
Schock
Sarah C
SC
Department of Cellular and Molecular Medicine, University of Ottawa, Ont., Canada.
Leblanc
Danielle
D
Hakim
Antoine M
AM
Thompson
Charlie S
CS
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000860:Hypoxia / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D000097004:Gap Junction delta-2 Protein
D000255:Adenosine Triphosphate; D017630:Connexins; D017868:Cyclic AMP-Dependent Protein Kinases; D054801:Phosphoinositide Phospholipase C; D011189:Potassium Chloride; D034741:RNA, Small Interfering; D018048:Receptors, Purinergic P2; D000097004:Gap Junction delta-2 Protein