We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Inhibition of protein kinase ( PK) C δ attenuates methamphetamine-induced dopaminergic toxicity via upregulation of phosphorylation of tyrosine hydroxylase at Ser<sup>40</sup> by modulation of protein phosphatase 2 A and PKA.
- 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
- Abstract
Recently, we proposed that inhibition of protein kinase ( PK) C δ 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 PKC δ inhibitor, or a PKC δ 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) 2 A activity. FTY720 (1 or 5 mg/kg, i.p., 1 h after the last MA administration), a PP2 A activator, significantly reversed the recovery in TH phosphorylation mediated by inhibition of PKC δ after MA treatment. Both H89 and FTY720 counteracted the recovery of MA-induced behavioural impairments induced by PKC δ 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 PKC δ inhibition-mediated attenuation of MA-induced impairment of TH phosphorylation. The results suggest that genetic or pharmacological inhibition of PKC δ requires modulation of PKA expression and/or PP2 A activity to attenuate the impairment of TH phosphorylation at Ser40 and behavioural activity induced by MA.
- Subjects
PROTEIN kinases; METHAMPHETAMINE; TYROSINE; HYDROXYLASES; PHOSPHORYLATION
- Publication
Clinical & Experimental Pharmacology & Physiology, 2015, Vol 42, Issue 2, p192
- ISSN
0305-1870
- Publication type
Article
- DOI
10.1111/1440-1681.12341