P3 - Striatal Phosphoproteins and the Actions of Psychostimulants

$294,378P01FY2011DANIH

Rockefeller University, New York NY

Investigators

Linked publications & trials

Paper 35872014 Paper 35554305 Paper 31363163 Paper 30185619 Paper 29802198 Paper 29357897 Paper 28613156 Paper 28507317 Paper 28167675 Paper 28115704 Paper 27998980 Paper 27616678 Paper 27510032 Paper 27457815 Paper 26733685 Paper 26639316 Paper 26370144 Paper 26334248 Paper 26320550 Paper 26192746 Paper 26099530 Paper 25639954 Paper 25476245 Paper 25349915 Paper 25259911 Paper 24920629 Paper 24725970 Paper 24525567 Paper 24311694 Paper 24189275 Paper 24143976 Paper 24089200 Paper 23781026 Paper 23690581 Paper 23640883 Paper 23623823 Paper 23419897 Paper 23415230 Paper 23290496 Paper 23255606 Paper 22753408 Paper 22357852 Paper 22250817 Paper 22046270 Paper 21922077 Paper 21904525 Paper 21833500 Paper 21331221 Paper 21096249 Paper 20890902 Paper 20682746 Paper 20664521 Paper 20643829 Paper 20631177 Paper 20463241 Paper 20403076 Paper 20236221 Paper 20181591 Paper 20156529 Paper 20145109 Paper 20106966 Paper 20100579 Paper 20056891 Paper 20007903 Paper 19901826 Paper 19759531 Paper 19666609 Paper 19651774 Paper 19396163 Paper 19300506 Paper 19246390 Paper 19218462 Paper 19202072 Paper 19158668 Paper 19017804 Paper 19017796 Paper 19013282 Paper 19013281 Paper 18923023 Paper 18823371 Paper 18760698 Paper 18687967 Paper 18622401 Paper 18496528 Paper 18467524 Paper 18439408 Paper 18399541 Paper 18367215 Paper 18287015 Paper 18256188 Paper 18088278 Paper 18032599 Paper 18005072 Paper 17698993 Paper 17686497 Paper 17622166 Paper 17608026 Paper 17606634 Paper 17596448 Paper 17553006

Abstract

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.

View original record on NIH RePORTER →