RGS proteins accelerate the deactivation of G protein coupled receptor initiated second messenger responses. The almost exclusive localization of RGS9L to the brain along with its high levels of expression in the striatum and nucleus accumbens suggest that this RGS protein could play a critical role in mediating the cellular response to drugs which alter dopaminergic neurotransmission. Such agents include drugs used for the treatment of neurological disorders (e.g. schizophrenia, migraine, Parkinson's and Huntington's disease) as well as drugs widely abused in our society (e.g. cocaine and amphetamine). The objectives of this proposal are to determine whether dopamine receptors mediate the amphetamine-induced changes in the expression of RGS9L and its target accessory proteins. In addition, this proposal seeks to determine whether such changes exhibit regional specificity. Our hypothesis is that RGS9L mRNA and protein expression is dynamically regulated by acute, direct receptor stimulation. The identification of genes that are differentially expressed in response to receptor-mediated stimuli (e.g. drugs of abuse) will provide likely candidates for biochemical mechanisms underlying drug-induced changes in brain activity. Determining the factors and pathways that regulate RGS expression will provide the basis for further studies assessing intracellular molecular events in more detail. These initial studies will make it possible to more specifically elucidate whether changes in the expression of RGS9L or its accessory proteins play a role in such adaptive responses as tolerance, dependence, and receptor desensitization.
|Cabrera-Vera, Theresa M; Hernandez, Salvador; Earls, Laurie R et al. (2004) RGS9-2 modulates D2 dopamine receptor-mediated Ca2+ channel inhibition in rat striatal cholinergic interneurons. Proc Natl Acad Sci U S A 101:16339-44|