期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 22, 期 1, 页码 247-256出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1460-9568.2005.04190.x
关键词
ageing; AMPA receptor; CaMKII; DARPP-32; dendrite; postsynaptic density; PP1
资金
- NIGMS NIH HHS [T32-GM08554, T32 GM008554] Funding Source: Medline
- NIMH NIH HHS [R01 MH45124, R01 MH63232, R01 MH063232, R01 MH57795, R01 MH045124] Funding Source: Medline
- NINDS NIH HHS [P01 NS044282, P01 NS044282-010002, NS044282, R01 NS37508] Funding Source: Medline
Nigrostriatal dopamine depletion disrupts striatal medium spiny neuron morphology in Parkinson's disease and modulates striatal synaptic plasticity in animal models of parkinsonism. We demonstrate that long-term nigrostriatal dopamine depletion in the rat induces evolving changes in the phosphorylation of striatal proteins critical for synaptic plasticity. Dopamine depletion increased the phosphorylation of the alpha isoform of calcium-calmodulin-dependent protein kinase II (CaMKII alpha) at Thr(286), a site associated with enhanced autonomous kinase activity, but did not alter total levels of CaMKII alpha or other synaptic proteins. Dopamine depletion decreased CaMKII alpha levels in postsynaptic density-enriched fractions without significant changes in other proteins. The activity of protein phosphatase 1 (PP1), a postsynaptic phosphatase that dephosphorylates CaMKII, is regulated by DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa). Dopamine depletion had no effect on DARPP-32 phosphorylation at Thr(34), but increased DARPP-32 phosphorylation at Thr(75). Levodopa administration reversed the increased phosphorylation of both CaMKII alpha and DARPP-32. Normal ageing increased the levels of PP1(gamma 1 isoform) but decreased levels of the PP1 gamma 1-targeting proteins spinophilin and neurabin. Elevated phosphorylations of CaMKII alpha and DARPP-32 were maintained for up to 20 months after dopamine depletion. However, phosphorylation of the CaMKII-PP1 substrate, Ser(831) in the glutamate receptor GluR1 subunit, was increased only after sustained (9-20 months) dopamine depletion. Interaction of ageing-related changes in PP1 with the dopamine depletion-induced changes in CaMKII alpha may account for enhanced GluR1 phosphorylation only after long-term dopamine depletion. These evolving changes may impact striatal synaptic plasticity, Parkinson's disease progression and the changing efficacy and side-effects associated with dopamine replacement therapy.
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