Title: Regulation of G protein-coupled receptor trafficking by downstream signaling kinases

Date: December 17th, 2015

Time: 2:00 p.m.

Location: Mellon Institute Social Room

Department: Biological Sciences, Carnegie Mellon University

Advisor: Manojkumar A. Puthenveedu

Abstract:

Our neurons rely on several diverse extracellular signals to sense our environment and produce responses that cause physiological and behavioral changes. Many of these signals, such as neurotransmitters, hormones, odorants, and light are transduced by the large family of signaling receptors, the G protein-coupled receptors (GPCRs). There is increasing evidence that the spatial location of a receptor within a cell controls sensitivity to signals and the type of cellular response that is produced. GPCR sensitivity and location within the cell is regulated by membrane trafficking of receptors, for example, endocytosis, or internalization of receptors from the cell surface to internal membrane compartments, or endosomes. Many questions remain about the functional consequences of post-endocytic sorting of GPCRs, the molecular mechanisms that govern this process, and how it is regulated in a physiological context. An emerging paradigm in GPCR biology is that GPCRs signal from endosomes, in addition to cell surface signaling, and the role of GPCR endosomal sorting in regulating this process is not well understood. This thesis investigates how phosphorylation of GPCRs by downstream signaling kinases regulates GPCR endosomal sorting and activity. Here, we show that phosphorylation of GPCRs by signaling kinases controls localization of GPCRs to endosomal microdomains to control initiation of endosomal G protein signaling. Further, our data suggest that the mu-opioid receptor (MOR), the target of endogenous endorphins and clinical opiates, undergoes opioid-selective sorting to distinct endosomal domains. Finally, we show that pain signaling enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Together, these results suggest that regulation of GPCR sorting by downstream signaling kinases controls spatial encoding of GPCR signaling and suggest a novel mode of homeostatic interaction between the pain and analgesic systems.

Thank you to my colleagues, friends, and mentors in the the CNBC community for making my time at CMU a great learning experience and a lot of fun!

Best wishes,

Shanna

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Shanna Bowersox Bowman

PhD Candidate

Department of Biological Sciences

Center for the Neural Basis of Cognition

Graduate Teaching Consultant,

Eberly Center for Teaching Excellence

Carnegie Mellon University

4400 5th Avenue

Pittsburgh, PA 15213