? The sorting of G protein-coupled receptors (GPCRs) is a fundamental mechanism that controls the regulation of receptors associated with serious neuropsychiatric disorders, including schizophrenia and depression. Our laboratory has recently shown that the cellular fate of receptors can be controlled by specific protein interaction of the C-termini of some GPCRs with GASP (GPCR-associated sorting protein) [Whistler, 2002 #1]. In particular, GPCRs that interact with GASP appear to be targeted to the degradative pathway and those receptors that do not interact with GASP recycle. Intriguingly, GASP binds to the C-termini of D2 receptors and not D1 receptors. Furthermore, in preliminary experiments we have shown that the D2 receptor is targeted for degradation unlike the recycling D1 receptor. D2 receptor antagonists are one of the primary therapeutic treatments for schizophrenia, implicating aberrant dopamine signaling in this disease. We hypothesize that the dopamine signaling pathway may be altered in the disease state as a consequence of the D2 receptor being targeted to the degradative pathway. We have designed and made dominant negative proteins that are able to inhibit GASP function both in vitro and in vivo and have developed an experimentally favorable in vitro cell model system and in vivo techniques suitable for testing this hypothesis. These studies will determine whether GPCR sorting can be manipulated both in vitro and in vivo. This may provide a new spectrum of therapeutic targets for the treatment of schizophrenia and depression. ? ?
