Nitric oxide/soluble guanylyl cyclase signaling mediates depolarization-induced protection of rat mesencephalic dopaminergic neurons from MPP+ cytotoxicity

Y. Kurauchi, A. Hisatsune, Y. Isohama, Tomohiro Sawa, T. Akaike, H. Katsuki

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


Neuronal electrical activity has been known to affect the viability of neurons in the central nervous system. Here we show that long-lasting membrane depolarization induced by elevated extracellular K+ recruits nitric oxide (NO)/soluble guanylyl cyclase/protein kinase G signaling pathway, induces 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP)-mediated protein S-guanylation, and confers dopaminergic neuroprotection. Treatment of primary mesencephalic cell cultures with 1-methyl-4-phenylpyridinium (MPP+) for 72h decreased the number of dopaminergic neurons, whereas the cell loss was markedly inhibited by elevated extracellular concentration of K+ (+40mM). The neuroprotective effect of elevated extracellular K+ was significantly attenuated by tetrodotoxin (a Na+ channel blocker), amlodipine (a voltage-dependent Ca2+ channel blocker), Nω-nitro-l-arginine methyl ester (l-NAME) (a nitric oxide synthase inhibitor), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (a soluble guanylyl cyclase inhibitor), and KT5823 or Rp-8-bromo-β-phenyl-1,N2-ethenoguanosine 3',5'-cyclic monophosphorothioate (Rp-8-Br-PET-cGMPS) (protein kinase G inhibitors). Elevated extracellular K+ increased 8-nitro-cGMP production resulting in the induction of protein S-guanylation in cells in mesencephalic cultures including dopaminergic neurons. In addition, exogenous application of 8-nitro-cGMP protected dopaminergic neurons from MPP+ cytotoxicity, which was prevented by zinc protoporphyrin IX, an inhibitor of heme oxygenase-1 (HO-1). Zinc protoporphyrin IX also inhibited the neuroprotective effect of elevated extracellular K+. On the other hand, KT5823 or Rp-8-Br-PET-cGMPS did not inhibit the induction of HO-1 protein expression by 8-nitro-cGMP, although these protein kinase G inhibitors abrogated the neuroprotective effect of 8-nitro-cGMP. These results suggest that protein S-guanylation (leading to HO-1 induction) as well as canonical protein kinase G signaling pathway plays an important role in NO-mediated, activity-dependent dopaminergic neuroprotection.

Original languageEnglish
Pages (from-to)206-215
Number of pages10
Publication statusPublished - 2013 Feb 2
Externally publishedYes


  • Cyclic GMP
  • Dopamine neurons
  • Heme oxygenase-1
  • Neuronal activity
  • Neuroprotection
  • Nitric oxide

ASJC Scopus subject areas

  • Neuroscience(all)


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