Considerable evidence indicates that the acute and chronic actions of psychomotor stimulants (e.g. cocaine and amphetamine), as well as of other drugs of abuse, involve modulation of neurotransmission in mesolimbic and nigrostriatal dopamine systems. Our previous studies have revealed that a family of substrates for cAMP-dependent protein kinase, including DARPP-32, RCS (Regulator of Calmodulin Signaling, previously termed ARPP-21), and ARPP-16, are highly enriched in medium spiny neurons of the basal ganglia, including the neostriatum and nucleus accumbens. Our ongoing research has also identified a new member of this family of striatal phosphoproteins as RaplGAP, a protein involved in the control of the small GTPase Rap. Other ongoing work has identified critical roles for novel isoforms of the serine/threonine protein phosphatase PP2A in control of the nucleo-cytoplasmic trafficking of DARPP-32, a process that is critical for the ability of DARPP-32 to mediate the actions of pyschostimulants. Moreover, we have found that ARPP-16 interacts with and may act to inhibit PP2A. Since the serine/threonine protein phosphatase, PPI, is a direct target for DARPP-32, and RCS controls PP2B activity indirectly, this work indicates that dopamine action in striatal neurons is likely to be largely mediated via the control of protein phosphatases. To address questions raised by these ongoing studies we propose two broad Specific Aims in Project 3 of the Program Project Grant.
In Aim I we will study the role of Rap GTPase, and its modulators RapGAP and EPAC in the actions of psychostimulants.
In Aim II we will study the role of novel isoforms of PP2A in the actions of psychostimulants.
Aim II will also include analysis of novel functions of PPI isoforms, the targets for DARPP-32 in striatal neurons. Results from our studies will complement the other two Projects of this Program Project grant. In addition, we will also carry out a number of collaborative studies with Projects 1 and 2, including studies of WAVEI phosphorylation with Project 1 and phosphoproteomic studies of mGluRS-dependent signaling in striatal neurons.
Together with the other projects, the proposed studies will lead to elucidation of the biochemical pathways through which drugs of abuse act in the brain, and to an increased likelihood that therapeutic agents will be developed that will prevent or reverse molecular adaptations within these pathways.
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