Receptor binding and autoradiographic studies detected different levels of various opioid receptors (ORs) in distinct brain and spinal regions known to be involved in pain sensation or analgesic responses and genetic knockout animals provided unambiguous evidence that the three OR genes perform distinct functions. The overall goal of this project is to understand """"""""when, where, and how much"""""""" of opioid receptor protein, specifically the kappaOR (KOR), is expressed in neurons under a physiological condition, and how is it regulated. It is hypothesized that KOR protein synthesis in neurons is regulated by a) transcriptional control that governs the birth of KOR neurons, and b) post-transcriptional control that determines when, where, and how many KOR molecules should be synthesized in neurons as needed. During the previous funding period, we carefully examined transcriptional regulation of KOR, that is primarily coupled to neuronal differentiation and includes the regulatory signals of vitamin A, nitric oxide, and the second messengers. We further uncovered several novel post-transcriptional regulatory pathways that are most relevant to the spatial control of the synthesis of KOR protein in neuronal compartments. In this renewal, we will first conduct mechanistic studies to address the novel findings of targeted KOR mRNA-transport, and its localized translational control in primary neurons. Secondly, we will extend the study of transcriptional regulatory mechanism of KOR gene by focusing on chromatin remodeling events. Thirdly, gene-targeted mouse models will be generated to address the pharmacological/physiological significance of KOR mRNA transport in neurons. We will learn: a) the genetic programming that sets the stage for KOR neurons to be born, b) the plasticity of KOR neurons to produce KOR proteins as needed, c) general and fundamental steps in neuronal gene silencing/activation at the level of chromatin remodeling, d) regulation of de novo synthesis of specific neuronal proteins in specialized neuronal compartments, and e) physiological and pharmacological relevance of localized synthesis of KOR in the context of whole animals. The potential to apply our findings and theories in the field of neuroscience, specifically the compartmentalized control of neuronal protein synthesis, can also be very significant such as in the fundamental mechanisms contributing to diseases like fragile X syndrome, neuromuscular disorders, Huntington Diseases (polyglutamate aggregates) and that implicated in long-term memory defects. ? ? ?
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