Regulation of Mu Opioid Receptor Signal Transduction

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DESCRIPTION (provided by applicant): Mu opioid receptors (MOR) play a major role in many functions, including pain pathways, the respiratory system, control of GI activity, the limbic (emotional) system and the reward system. They are the target of clinically important drugs, such as morphine and codeine. Our understanding of how MOR function is regulated is incomplete. In preliminary studies, we discovered dramatic changes in the function of MOR during the development of rat brain, changes far greater than any we have seen studying other neurotransmitter systems. This suggested that this developmental paradigm would provide novel and interesting information about regulation of function within this system, information relevant not only to development but also to MOR function in adult animals. Based upon our preliminary data, we hypothesize that the dramatic changes in organization and maturation of the MOR in developing striatum are governed and regulated by changes in the expression of other proteins interacting with MOR. Specific Aim 1 is to examine the role of G protein expression on the development of MOR function. These studies include analysis of the developmental expression of the G protein subtypes with which MOR interact, analysis of which specific G protein subtypes interact with MOR at several stages during development, and how these interactions change quantitatively. Specific Aim 2 is to examine the interaction of MOR with other proteins, which may play a role in regulating MOR functional activity. These studies initially focus on the interaction of MOR with RanBPM, a protein initially identified by yeast two-hybrid screen as interacting with the MOR C-terminal tail. Our preliminary data support this hypothesis, indicating RanBPM modulates the signal transduction functions of MOR. This aim examines this interaction in detail, analyzes which domains of these two proteins are important for the interaction, and investigates the role of RanBPM in the changes in MOR function found during development. We think these studies will provide important information about what regulates MOR function during development and that these results also will provide insight into MOR function in the mature animal. Further understanding of the regulation of MOR function is relevant not only to development but to clinical situations involving drugs interacting with MOR, such as pain, diarrhea and drug dependence.