Inhibition of protein kinase (PK) Cδattenuates methamphetamine-induced dopaminergic toxicity via upregulation of phosphorylation of tyrosine hydroxylase at Ser40by modulation of protein phosphatase 2A and PKA

Autor:	Ji Hoon Jeong, Hyoung-Chun Kim, Eun-Joo Shin, Toshitaka Nabeshima, Chu X. Duong, Seung Yeol Nah, Yunsung Nam, Yong Kwang Lim, Choon-Gon Jang, Duy Khanh Dang
Rok vydání:	2015
Předmět:	medicine.medical_specialty Tyrosine 3-Monooxygenase Physiology Dopamine p38 mitogen-activated protein kinases Phosphatase Biology Methamphetamine Mice chemistry.chemical_compound Physiology (medical) Internal medicine medicine Animals Benzopyrans Protein Phosphatase 2 Phosphorylation Extracellular Signal-Regulated MAP Kinases Protein kinase A Protein Kinase Inhibitors Mice Knockout Pharmacology Tyrosine hydroxylase Kinase Intracellular Signaling Peptides and Proteins JNK Mitogen-Activated Protein Kinases Acetophenones Protein phosphatase 2 Cyclic AMP-Dependent Protein Kinases Up-Regulation Mice Inbred C57BL Protein Kinase C-delta Endocrinology chemistry Calcium Mitogen-Activated Protein Kinases Calcium-Calmodulin-Dependent Protein Kinase Type 2 Rottlerin
Zdroj:	Clinical and Experimental Pharmacology and Physiology. 42:192-201
ISSN:	0305-1870
Popis:	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 Ser(40) in the striatum, but not in the phosphorylation of TH at Ser(31) . 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 Ser(40) 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 Ser(40) and behavioural activity induced by MA.
Databáze:	OpenAIRE
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