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. (February 2015)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Clinical and experimental pharmacology and physiology. Volume 42:Number 2(2015:Feb.)
• Page Start: 192
• Page End: 201
• Publication Date: 2015-02
• Subjects: Clinical pharmacology -- Periodicals; Pharmacology, Experimental -- Periodicals; Physiology, Experimental -- Periodicals; Physiology, Pathological -- Periodicals; 615.1
• DOI: 10.1111/1440-1681.12341
• Languages: English
• ISSNs: 0305-1870

Abstract

<abstract abstract-type="main" id="cep12341-abs-0001"> <title>Summary</title> <p>Recently, we proposed that inhibition of protein kinase (PK) C<italic>δ</italic> 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<sup>40</sup> in the striatum, but not in the phosphorylation of TH at Ser<sup>31</sup>. In the present study, treatment with rottlerin (1.5 or 3.0 μg, i.c.v, once a day for 5 days), a PKC<italic>δ</italic> inhibitor, or a PKC<italic>δ</italic> antisense oligonucleotide (ASO; 2.5 μg/μl, i.c.v., 3 times) significantly attenuated MA‐induced reductions in the phosphorylation of TH at Ser<sup>40</sup> 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 PKC<italic>δ</italic> after MA treatment. Both H89 and FTY720 counteracted the recovery of MA‐induced behavioural impairments induced by PKC<italic>δ</italic> inhibition. The effects, mediated by rottlerin or ASO in MA‐treated wild‐type mice were comparable with those in MA‐treated <italic>PKCδ</italic><sup><italic>−/−</italic></sup> 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 PKC<italic>δ</italic> inhibition‐mediated attenuation of MA‐induced impairment of TH phosphorylation. The results suggest that genetic or pharmacological inhibition of PKC<italic>δ</italic> requires modulation of PKA expression and/or PP2A activity to attenuate the impairment of TH phosphorylation at Ser<sup>40</sup> and behavioural activity induced by MA.</p> </abstract>