G protein-coupled receptors (GPCRs) comprise one of the most therapeutically attractive family of signaling receptors. They have critical roles in regulating cellular signaling pathways and function and targeting these receptors have been proved beneficial for the treatment of a variety of diseases. Therefore, significant effort is aimed at the elucidation of the mechanisms behind ligand-specific trafficking, signaling, and functional selectivity. The latter is an important pharmacological concept that describes the property of ligands to activate specific cellular signaling mechanisms with distinct cellular responses. G protein and β-arrestin signaling pathway regulation have been proposed as targets of functional selectivity. It has been suggested that ligands that are biased towards one pathway over the other have improved therapeutic efficacy by reducing unwanted side effects. One of the GPCRs that needs further studies is the cannabinoid receptor 2 (CB2R). Ligands targeting CB2R have shown therapeutic potential in preclinical models of neuroinflammatory and neurodegenerative conditions, however, CB2R-based therapies have fared poorly in clinical trials. This dissertation was aimed to characterize the molecular events regulating CB2R signaling and receptor cellular distribution and hope to shed light into the fundamental mechanisms controlling CB2R physiological functions. Therefore, the main hypothesis of this research work is that ligand-mediated CB2R signaling activation is regulated by receptor trafficking and subcellular location.
Chapter 1 provides a general background on GPCR trafficking and signaling regulation and focuses on CB2R therapeutic potential and describes why it is important to understand the molecular mechanisms controlling CB2R signaling. Chapter 2 includes published data where we investigated intracellular signaling form CB2R and elucidate the role of the retromer complex in terminating β-arrestin mediated signaling from CB2R. Lastly, Chapter 3 provides an expanded discussion to chapter 2, addresses the limitations of our model and presents future experiments supported by preliminary data on Appendices II-IV.
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|Advisor:||Yudowski, Guillermo A.|
|Commitee:||Diaz, Manuel, Jimenez, Carlos, Miranda, Jorge D., Silva, Walter I.|
|School:||University of Puerto Rico Medical Sciences (Puerto Rico)|
|School Location:||United States -- Puerto Rico|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Subjects:||Biology, Molecular biology, Pharmacology|
|Keywords:||Beta-arrestin signaling, Cannabinoid receptor 2, G protein coupled receptor, Receptor trafficking, TIRF microscopy|
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