RESUMO
Metabotropic glutamate (mGlu) receptors in the basal ganglia motor loop may increase cell excitability (Group I) or modulate neurotransmitter release (Group I, II and III). Nigrostriatal tract degeneration in Parkinson's disease (PD) produces downstream pathological disturbances in glutamate and GABA transmission. The present study examined whether changes in mGlu receptor gene expression may either contribute to, or compensate for these pathological changes in transmission. In situ hybridisation studies examined the levels of mGlu receptor mRNA in motor loop regions in rats bearing a 6-hydroxydopamine-induced unilateral nigrostriatal tract lesion. Gene expression was reduced in the lesion compared to intact hemispheres for mGlu(1) in the substantia nigra pars compacta (SNc; 51.8+/-11.5%), mGlu(3) in the striatum and globus pallidus (11.7+/-2.8% and 18.9+/-1.4%, respectively) and mGlu(4) in the striatum and premotor cortex (13.8+/-2.7% and 15.8+/-5.5%, respectively). Loss of mGlu(1) mRNA in the SNc confirms that mGlu(1) is highly expressed on dopaminergic neurones where it may contribute to their vulnerability in PD. The down-regulation of mGlu(3) and mGlu(4) mRNA may reflect reduced transcriptional activity in response to increased levels of extracellular glutamate in these regions under parkinsonian conditions. These changes are likely to exacerbate the pathophysiological glutamate and GABA transmission within these regions in PD.
Assuntos
Gânglios da Base/metabolismo , Regulação da Expressão Gênica/fisiologia , Receptores de Glutamato Metabotrópico/biossíntese , Receptores de Glutamato Metabotrópico/genética , Substância Negra/metabolismo , Animais , Corpo Estriado/metabolismo , Masculino , Vias Neurais/metabolismo , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5RESUMO
Dishevelled has been implicated in the regulation of cell fate decisions, cell polarity, and neuronal function. However, the mechanism of Dishevelled action remains poorly understood. Here we examine the cellular localization and function of the mouse Dishevelled protein, DVL-1. Endogenous DVL-1 colocalizes with axonal microtubules and sediments with brain microtubules. Expression of DVL-1 protects stable microtubules from depolymerization by nocodazole in both dividing cells and differentiated neuroblastoma cells. Deletion analyses reveal that the PDZ domain, but not the DEP domain, of DVL-1 is required for microtubule stabilization. The microtubule stabilizing function of DVL-1 is mimicked by lithium-mediated inhibition of glycogen synthase kinase-3beta (GSK-3beta) and blocked by expression of GSK-3beta. These findings suggest that DVL-1, through GSK-3beta, can regulate microtubule dynamics. This new function of DVL-1 in controlling microtubule stability may have important implications for Dishevelled proteins in regulating cell polarity.