CHAPTER 9: Protein Interactions with Dopamine Receptors as Potential New Drug Targets for Treating Schizophrenia

One strategy for developing new treatments is to focus on the neural signaling pathways implicated in the pathophysiology of schizophrenia. Dysfunction within the dopamine neurotransmitter system has been widely linked to the pathophysiology of schizophrenia. The classical target of existing antipsychotic medications for schizophrenia is the D2 dopamine receptor (D2R). Most effective antipsychotics for schizophrenia principally antagonize the D2R subtype. The dopamine receptor family is a functionally diverse class of G-protein-coupled receptors (GPCR), present throughout the nervous system. The classical view of GPCR function is that downstream effects are mediated almost exclusively by G-protein-dependent pathways. The recent discovery of interactions between the dopamine receptors and various other receptors and regulatory proteins points to alternative signaling routes. Using yeast two-hybrid, co-immunoprecipitation, glutathione-S-transferase pull-down, and in vitro binding assays, more than 20 dopamine receptor interacting proteins have been determined, many of which are relevant to schizophrenia. These proteins selectively regulate specific signaling pathways and functions of dopamine receptors via protein–protein interactions, without affecting other signaling pathways and dopamine receptor functions. Thus, targeting protein–protein interactions represents a promising alternative treatment strategy for schizophrenia, which might avoid the side-effects of existing antipsychotics that simply block the ligand-binding site of the dopamine receptor. In this chapter, we discuss the proteins that interact with dopamine receptors, regulatory mechanisms for these interactions, and promising avenues for future research into novel drugs for schizophrenia.