Assemblies of glutamate receptor subunits with post-synaptic density proteins and their alterations in Parkinson's disease.
N-methyl-D-aspartate (NMDA) receptors have been implicated as a mediator of neuronal injury associated with many neurological disorders including ischemia, epilepsy, brain trauma, dementia and neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease. To this, non-selective NMDA receptor antagonists have been tried and have been shown to be effective in many experimental animal models of disease, and some of these compounds have moved into clinical trials. However, the initial enthusiasm for this approach has waned, because the therapeutic index for most NMDA antagonists is quite poor, with significant adverse effects at clinically effective doses, thus limiting their utility. More recently, the concept that the exact pathways downstream NMDA receptor activation could represent a key variable element among neurological disorders has been put forward. In particular, variations in NMDA receptor subunit composition could be important in different disorders, both in the pathophysiological mechanisms of cell death and in the application of specific symptomatic therapies. As to PD, NMDA receptor complex has been shown to be altered in experimental models of parkinsonism and in PD in humans. Further, it has become increasingly evident that the NMDA receptor complex is intimately involved in the regulation of corticostriatal long-term potentiation, which is altered in experimental parkinsonism. The following sections will examine the modifications of specific NMDA receptor subunits as well as post-synaptic associated signalling complex including kinases and scaffolding proteins in experimental parkinsonism. These findings may allow the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for PD.
Gardoni
Fabrizio
F
Department of Pharmacological Sciences, University of Milano, Milano, Italy.
Ghiglieri
Veronica
V
Di Luca
Monica
M
Calabresi
Paolo
P
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D051528:Guanylate Kinases / Q000378:metabolism*; D006801:Humans; D008251:Macaca; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology*; D010300:Parkinson Disease / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure
D051528:Guanylate Kinases; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor