Nitric oxide activates extracellular signal-regulated kinase 1/2 and enhances declustering of ionotropic glutamate receptor subunit 2/3 in rat cerebellar Purkinje cells.
Exogenous nitric oxide (NO) donors (S-nitroso-N-acetyl-DL-penicillamine and (E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide) and simultaneous application of high potassium and glutamate led to the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in cerebellar Purkinje cells. NO-induced ERK1/2 phosphorylation was abolished by the addition of MEK (MAPK ERK kinase) inhibitor (PD98059) or oxyhemoglobin, and was significantly reduced by the PKG (cGMP-dependent protein kinase) inhibitor, KT5823. KT5823 also reduced the peak levels of ERK1/2 activation induced by high K-glutamate or NO in Purkinje cell somata. NO-induced ERK1/2 phosphorylation remained above basal levels for at least 1 h after NO-donor removal. To address the physiological role of NO-induced ERK activation in Purkinje cells, we examined the effects of NO and 8-bromoadenosine 3', 5'-cyclic monophosphate (8-Br-cGMP) on PKC-dependent receptor declustering, which underlies cerebellar long-term depression. TPA (12-Ø-tetradecanoylphorbol 13-acetate), a potent activator of PKC, induced GluR2/3 receptor declustering. The 8-Br-cGMP or NO-donors enhanced GluR2/3 declustering, but did not induce it. These results suggest an important role for the NO-cGMP-PKG pathway in the activation of ERK1/2 and GluR2/3 (ionotropic glutomate receptor subunit 2/3) declustering in Purkinje cells.
Endo
Shogo
S
Neuronal Circuit Mechanisms Research Group, RIKEN Brain Science Institute, Wako 351-0198, Japan. sendo@riken.jp
Launey
Thomas
T
D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*
D020030:Nitric Oxide Donors; D018091:Receptors, AMPA; C104723:glutamate receptor ionotropic, AMPA 3; D009569:Nitric Oxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C104722:glutamate receptor ionotropic, AMPA 2