title: DOR activation inhibits anoxic/ischemic Na+ influx through Na+ channels via PKC mechanisms in the cortex.
abstract: Activation of delta-opioid receptors (DOR) is neuroprotective against hypoxic/ischemic injury in the cortex, which is at least partially related to its action against hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal injury. Na(+) influx through TTX-sensitive voltage-gated Na(+) channels may be a main mechanism for hypoxia-induced disruption of K(+) homeostasis, with DOR activation attenuating the disruption of ionic homeostasis by targeting voltage-gated Na(+) channels. In the present study we examined the role of DOR in the regulation of Na(+) influx in anoxia and simulated ischemia (oxygen-glucose deprivation) as well as the effect of DOR activation on the Na(+) influx induced by a Na(+) channel opener without anoxic/ischemic stress and explored a potential PKC mechanism underlying the DOR action. We directly measured extracellular Na(+) activity in mouse cortical slices with Na(+) selective electrodes and found that (1) anoxia-induced Na(+) influx occurred mainly through TTX-sensitive Na(+) channels; (2) DOR activation inhibited the anoxia/ischemia-induced Na(+) influx; (3) veratridine, a Na(+) channel opener, enhanced the anoxia-induced Na(+) influx; this could be attenuated by DOR activation; (4) DOR activation did not reduce the anoxia-induced Na(+) influx in the presence of chelerythrine, a broad-spectrum PKC blocker; and (5) DOR effects were blocked by PKCβII peptide inhibitor, and PKCθ pseudosubstrate inhibitor, respectively. We conclude that DOR activation inhibits anoxia-induced Na(+) influx through Na(+) channels via PKC (especially PKCβII and PKCθ isoforms) dependent mechanisms in the cortex.
authors.affiliation: The Third Medical College of Soochow University, Changzhou, Jiangsu 213003, PR China.
authors.forename: Dongman
authors.initials: D
authors.lastname: Chao
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: He
authors.forename: Yilin
authors.initials: Y
authors.lastname: Yang
authors.forename: Alia
authors.initials: A
authors.lastname: Bazzy-Asaad
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.forename: Dong H
authors.initials: DH
authors.lastname: Kim
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism*; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D010296:Parietal Lobe / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D064546:Protein Kinase C beta; D000074121:Protein Kinase C-theta; D017465:Receptors, Opioid, delta / Q000378:metabolism* / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D017465:Receptors, Opioid, delta; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D000074121:Protein Kinase C-theta