Olfactory Receptor Dimerization 公开
Bush, Cristina Fae (2008)
Abstract
Olfactory receptors (ORs) comprise the largest subfamily of G protein- coupled receptors (GPCRs) and are responsible for the initiation of olfactory perception. In the olfactory epithelium, ORs are found at the plasma membrane of olfactory sensory neurons, localized to cilia that extend into the nasal cavity and exposed to the external environment. In this manner, ORs are readily accessible to bind inhaled environmental chemicals that serve as ligands and initiate signaling cascades that result in olfactory perception. Additionally, ORs may be involved in other aspects of chemodetection in the body, as a growing number of non-olfactory tissues including the prostate, spermatids, and developing heart also exhibit OR expression. Despite intense interest over the past two decades in better understanding OR properties, characterization of OR pharmacology, biochemistry, and signaling mechanisms has been limited. A key obstacle hindering the study of ORs has been difficulty in efficiently expressing these receptors in heterologous cells. When expressed in common cell culture systems, the bulk of OR proteins are retained in the endoplasmic reticulum, with very little of the receptor localizing to the plasma membrane. The central hypothesis of this work is that ORs expressed in heterologous cells lack one or more critical components present in native cells that are required for proper localization. The studies presented here demonstrate that some ORs can heterodimerize with specific non-OR GPCRs, which results in significantly enhanced plasma membrane localization of ORs. Moreover, some of these receptor-receptor interactions can influence the G protein coupling specificity of ORs. In addition to heterodimerization with non-OR GPCRs, the data presented here demonstrate that ORs also possess the capacity to homodimerize as well as heterodimerize with other ORs. Collectively, these data reveal previously-unappreciated receptor-receptor interactions that can significantly influence OR functionality. The findings presented here provide a means by which certain ORs can be effectively expressed in heterologous cells and shed light on fundamental aspects of OR biology.
Table of Contents
Chapter 1: Introduction
1.1 Olfaction
1.2 The mammalian olfactory epithelium
1.3 Olfactory signaling in mammals
1.4 Identification of the olfactory receptor gene family
1.4.1 Olfactory receptor genes and proteins
1.4.2 Olfactory receptor expression outside of the olfactory epithelium
1.5 Olfactory receptor pharmacology
1.5.1 Regulation of olfactory receptors by kinases and arrestins
1.6 Trafficking difficulties of G protein coupled receptors as a whole
1.6.1 An olfactory receptor chaperone in C. elegans
1.6.2 Heterodimerization as an influence on olfactory receptor trafficking
1.6.2.1 The role of heterodimerization in Drosophila olfactory receptor trafficking
1.7 Neurotransmitter regulation of olfaction
1.8 Objectives of this dissertation
Chapter 2: Olfactory Receptor Interactions with Adrenergic Receptors
2.1 Introduction
2.2 Experimental procedures
2.3 Results
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