title: Neuroprotection of GluK1 kainate receptor agonist ATPA against ischemic neuronal injury through inhibiting GluK2 kainate receptor-JNK3 pathway via GABA(A) receptors.
abstract: It is well known that GluK2-containing kainate receptors play essential roles in seizure and cerebral ischemia-induced neuronal death, while GluK1-containing kainate receptors could increase tonic inhibition of post-synaptic pyramidal neurons. This research investigated whether GluK1 could inhibit activation of c-Jun N-terminal kinase 3 (JNK3) signaling pathway mediated by the GluK2 in cerebral ischemia-reperfusion. The results show that GluK1 activation by (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA) at 1nmol per rat could inhibit the assembly of GluK2·Postsynaptic density 95·mixed lineage kinase 3 signaling module, activation of JNK3 and its downstream signal molecules. However, the inhibition of ATPA could be prevented by GluK1 antagonist NS3763, GluK1 antisense, and GABA(A) receptor antagonist bicuculline. In addition, ATPA played a neuroprotective role against cerebral ischemia. In sum, the findings indicate that activation of GluK1 by ATPA at specific dosages may promote GABA release, which then suppresses post-synaptic GluK2-JNK3 signaling-mediated cerebral ischemic injury via GABA(A)R.
authors.affiliation: Research Center for Biochemistry and Molecular Biology, Jiangsu Key Laboratory of Brain Disease Bio-information, Xuzhou Medical College, Xuzhou 221002, Jiangsu, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lv
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Zong
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D048057:Mitogen-Activated Protein Kinase 10 / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000819:agonists* / Q000187:drug effects / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000097806:GluK2 Kainate Receptor
chemical_list: D007555:Isoxazoles; D048057:Mitogen-Activated Protein Kinase 10; D018696:Neuroprotective Agents; D011422:Propionates; D011963:Receptors, GABA-A; D018092:Kainic Acid Receptors; D005680:gamma-Aminobutyric Acid; D000097806:GluK2 Kainate Receptor; C081662:alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate