Inhibition of protein kinase (PK) Cδ attenuates methamphetamine-induced dopaminergic toxicity via upregulation of phosphorylation of tyrosine hydroxylase at Ser40 by modulation of protein phosphatase 2A and PKA

Duy Khanh Dang, Chu X. Duong, Yunsung Nam, Eun Joo Shin, Yong Kwang Lim, Ji Hoon Jeong, Choon Gon Jang, Seung Yeol Nah, Toshitaka Nabeshima, Hyoung Chun Kim

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Abstract

Recently, we proposed that inhibition of protein kinase (PK) Cδ may be a useful target for protection against methamphetamine (MA)-induced dopaminergic toxicity. We demonstrated that treatment with MA resulted in a significant decrease in phosphorylation of tyrosine hydroxylase (TH) at Ser40 in the striatum, but not in the phosphorylation of TH at Ser31. In the present study, treatment with rottlerin (1.5 or 3.0 μg, i.c.v, once a day for 5 days), a PKCδ inhibitor, or a PKCδ antisense oligonucleotide (ASO; 2.5 μg/μl, i.c.v., 3 times) significantly attenuated MA-induced reductions in the phosphorylation of TH at Ser40 and in the expression of PKA in the striatum of mice. This attenuation was significantly counteracted by H89 (10 or 30 ng, i.c.v., 1 h after the last MA administration), a PKA inhibitor. Treatment with rottlerin or ASO significantly attenuated the MA-induced increase in protein phosphatase (PP) 2A activity. FTY720 (1 or 5 mg/kg, i.p., 1 h after the last MA administration), a PP2A activator, significantly reversed the recovery in TH phosphorylation mediated by inhibition of PKCδ after MA treatment. Both H89 and FTY720 counteracted the recovery of MA-induced behavioural impairments induced by PKCδ inhibition. The effects, mediated by rottlerin or ASO in MA-treated wild-type mice were comparable with those in MA-treated PKCδ-/- mice. However, neither inhibition of the mitogen-activated protein kinase subfamily (extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38) nor inhibition of calcium calmodulin kinase II significantly altered PKCδ inhibition-mediated attenuation of MA-induced impairment of TH phosphorylation. The results suggest that genetic or pharmacological inhibition of PKCδ requires modulation of PKA expression and/or PP2A activity to attenuate the impairment of TH phosphorylation at Ser40 and behavioural activity induced by MA.

Original languageEnglish
Pages (from-to)192-201
Number of pages10
JournalClinical and Experimental Pharmacology and Physiology
Volume42
Issue number2
DOIs
Publication statusPublished - 01-02-2015

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Protein Phosphatase 2
Methamphetamine
Tyrosine 3-Monooxygenase
Protein Kinase C
Up-Regulation
Phosphorylation
Calcium-Calmodulin-Dependent Protein Kinases
JNK Mitogen-Activated Protein Kinases
Antisense Oligonucleotides
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinases

All Science Journal Classification (ASJC) codes

  • Physiology
  • Pharmacology
  • Physiology (medical)

Cite this

Dang, Duy Khanh ; Duong, Chu X. ; Nam, Yunsung ; Shin, Eun Joo ; Lim, Yong Kwang ; Jeong, Ji Hoon ; Jang, Choon Gon ; Nah, Seung Yeol ; Nabeshima, Toshitaka ; Kim, Hyoung Chun. / Inhibition of protein kinase (PK) Cδ attenuates methamphetamine-induced dopaminergic toxicity via upregulation of phosphorylation of tyrosine hydroxylase at Ser40 by modulation of protein phosphatase 2A and PKA. In: Clinical and Experimental Pharmacology and Physiology. 2015 ; Vol. 42, No. 2. pp. 192-201.
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abstract = "Recently, we proposed that inhibition of protein kinase (PK) Cδ may be a useful target for protection against methamphetamine (MA)-induced dopaminergic toxicity. We demonstrated that treatment with MA resulted in a significant decrease in phosphorylation of tyrosine hydroxylase (TH) at Ser40 in the striatum, but not in the phosphorylation of TH at Ser31. In the present study, treatment with rottlerin (1.5 or 3.0 μg, i.c.v, once a day for 5 days), a PKCδ inhibitor, or a PKCδ antisense oligonucleotide (ASO; 2.5 μg/μl, i.c.v., 3 times) significantly attenuated MA-induced reductions in the phosphorylation of TH at Ser40 and in the expression of PKA in the striatum of mice. This attenuation was significantly counteracted by H89 (10 or 30 ng, i.c.v., 1 h after the last MA administration), a PKA inhibitor. Treatment with rottlerin or ASO significantly attenuated the MA-induced increase in protein phosphatase (PP) 2A activity. FTY720 (1 or 5 mg/kg, i.p., 1 h after the last MA administration), a PP2A activator, significantly reversed the recovery in TH phosphorylation mediated by inhibition of PKCδ after MA treatment. Both H89 and FTY720 counteracted the recovery of MA-induced behavioural impairments induced by PKCδ inhibition. The effects, mediated by rottlerin or ASO in MA-treated wild-type mice were comparable with those in MA-treated PKCδ-/- mice. However, neither inhibition of the mitogen-activated protein kinase subfamily (extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38) nor inhibition of calcium calmodulin kinase II significantly altered PKCδ inhibition-mediated attenuation of MA-induced impairment of TH phosphorylation. The results suggest that genetic or pharmacological inhibition of PKCδ requires modulation of PKA expression and/or PP2A activity to attenuate the impairment of TH phosphorylation at Ser40 and behavioural activity induced by MA.",
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Inhibition of protein kinase (PK) Cδ attenuates methamphetamine-induced dopaminergic toxicity via upregulation of phosphorylation of tyrosine hydroxylase at Ser40 by modulation of protein phosphatase 2A and PKA. / Dang, Duy Khanh; Duong, Chu X.; Nam, Yunsung; Shin, Eun Joo; Lim, Yong Kwang; Jeong, Ji Hoon; Jang, Choon Gon; Nah, Seung Yeol; Nabeshima, Toshitaka; Kim, Hyoung Chun.

In: Clinical and Experimental Pharmacology and Physiology, Vol. 42, No. 2, 01.02.2015, p. 192-201.

Research output: Contribution to journalArticle

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T1 - Inhibition of protein kinase (PK) Cδ attenuates methamphetamine-induced dopaminergic toxicity via upregulation of phosphorylation of tyrosine hydroxylase at Ser40 by modulation of protein phosphatase 2A and PKA

AU - Dang, Duy Khanh

AU - Duong, Chu X.

AU - Nam, Yunsung

AU - Shin, Eun Joo

AU - Lim, Yong Kwang

AU - Jeong, Ji Hoon

AU - Jang, Choon Gon

AU - Nah, Seung Yeol

AU - Nabeshima, Toshitaka

AU - Kim, Hyoung Chun

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