Project entitled """"""""Physiological, Anatomical and Cell Biological Regulation of Phosphoproteins in the Basal Ganglia,"""""""" focuses on elucidating the molecular mechanisms whereby dopamine regulates neurotransmitter receptors and voltage-gated ion channels in the neostriatum. In particular, we will study protein phosphatase-12 (PP1) and its regulatory proteins, DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, Mr 32 kD), spinophilin and neurabin using the tools of electrophysiology and microscopy, in conjunction with gene-targeting (Project IV).
Specific Aim I will be to characterize the roles of these proteins in the dopaminergic regulation of AMPA, NMDA, GABAA and voltage-gated Ca2+ channels in mice bearing gene-disruptions of PP1, DARPP-32, spinophilin or neurabin. We will also examine potential aberrations in the dopamine-mediate regulation of synaptic transmission and plasticity in the gene-disrupted mice.
Specific Aim II will be to study the subcellular and regional distribution of neurabin in the brain to provide insight into all the physiological role of this newly discovered protein. Moreover, we will investigate the roles of neurabin, spinophilin and PP1 in the regulation of neuronal morphology.
Specific Aim III will be to determine how spinophilin is targeted in the vicinity of ion channels and how the localization of the spinophilin-PP1 and neurabin-PP1 complexes is dynamically regulated in neurons. Elucidation of these three aims is essential for understanding the molecular and cellular basis of dopamine action and may result in new opportunities for the treatment of dopamine-related neurodegenerative and neuropsychiatric diseases.
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