Date

8-1-2012

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Biochemistry and Molecular Biology

Institution

Oregon Health & Science University

Abstract

G protein-coupled receptors (GPCRs) serve as conduits for dissemination of information across the cell membrane. Many pharmaceutical drugs act through these receptors to produce their therapeutic effects. Understanding how drugs can manipulate these bio- machines has been one of my long-standing passions. The overarching goal of this dissertation is to explore receptor mechanisms of activation using reductionist approaches. In pursuing this goal, I established new ways to work with the receptor. These techniques included purifying the receptor (Chapter 2) and studying dynamic structural changes using fluorescence spectroscopic approaches, with special emphasis on understanding how an intriguing allosteric ligand affects CB1 (Chapter 3). In Chapter 4, I cover my investigation of the structure and role of the long N-terminus. Finally, using the purified CB1 receptor as an antigen, I created and characterized several novel CB1 specific antibodies, one of which is conformationally sensitive and shows an allosteric effect on the receptor (Chapter 5). This introductory review will encompass many wide aspects of GPCR research, with a focus on pharmacological probes, structure, and the cannabinoid receptor system. I will begin with the initial discovery of cannabinoid receptors, and then focus on the neuronal cannabinoid receptor, CB1. I have provided an overview of some of the commonly used ligands that bind to CB1 and briefly describe some general physiological roles of this receptor in the body. I will then highlight some aspects of GPCR structure/function, and finally conclude with a discussion of allosteric modulation and biased signaling in GPCRs. In an effort to keep the introduction concise, I have provided more in-depth mathematical analyses of allosteric models in the appendix.

Identifier

doi:10.6083/M4NG4NNF

School

School of Medicine

Available for download on Sunday, October 01, 2017

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