Canadian Association of Neurosciences Review: the role of dopamine receptor function in neurodegenerative diseases.

Dopamine (DA) receptors, which are heavily expressed in the caudate/putamen of the brain, represent the molecular target of several drugs used in the treatment of various neurological disorders, such as Parkinson's disease. Although most of the drugs are very effective in alleviating the symptoms associated with these conditions, their long-term utilization could lead to the development of severe side-effects. In addition to uncovering novel mediators of physiological DA receptor functions, recent research advances are suggesting a role of these receptors in toxic effects on neurons. For instance, accumulating evidence indicates that DA receptors, particularly D1 receptors, are central in the neuronal toxicity induced by elevated synaptic levels of DA. In this review, we will discuss recent findings on DA receptors as regulators of long term neuronal dysfunction and neurodegenerative processes.

Calcium-independent phospholipase A(2) influences AMPA-mediated toxicity of hippocampal slices by regulating the GluR1 subunit in synaptic membranes.

We have recently documented that phosphorylation of the GluR1 subunit of alpha-amino-3-hydroxy-5-methylisoxazole-propionate (AMPA) glutamate receptors is influenced by calcium-independent forms of phospholipase A(2) (iPLA(2)) activity in the brain. Given the importance of GluR1 subunit phosphorylation in the control of AMPA receptor delivery to synaptic membranes, we tested the influence of iPLA(2) activity on AMPA receptor distribution between neuronal compartments, using organotypic cultured hippocampal slices. In agreement with earlier reports, the iPLA(2) inhibitor bromoenol lactone (BEL) markedly enhanced the phosphorylation of the GluR1 subunit at both Ser831 and Ser845 residues. GluR1 subunit phosphorylation levels were selectively increased by (R)-BEL, an enantio-selective inhibitor of iPLA(2)gamma, but not by (S)-BEL, an iPLA(2)beta inhibitor. The iPLA(2)gamma inhibitor R-BEL also promoted the insertion of new GluR1 subunits into synaptic membranes and exacerbated AMPA-mediated cell death in the CA1 region of the hippocampus. The latter effect was selectively abolished by IEM 1460 and philanthotoxin-433, two antagonists specific for AMPA receptors lacking GluR2 subunits. These results provide evidence that iPLA(2)gamma-related regulation of AMPA receptor GluR1 subunit phosphorylation could represent an important mechanism modulating hippocampal cell death induced by AMPA receptor overstimulation.