G-protein coupled receptors (GPCRs) are seven transmembrane (TM) proteins which play essential roles in converting extracellular stimuli into intracellular signals in a variety of cell types. Odor detection by olfactory sensory neurons (OSNs) in the mammalian nose also depends on a large family of G-protein coupled odorant receptors (ORs), which are further classified into >200 subfamilies based on sequence homology. The mouse olfactory epithelium harbors a few million OSNs and each neuron expresses a single OR type from a repertoire of ~1200. Despite the well-characterized, G-protein mediated signal transduction cascade that leads to activation of OSNs upon odor stimulation, little is known about the molecular and structural basis of OR activation. Recent studies have revealed two important features of ORs and their host OSNs, which have important implications for GPCR function and odor information processing. (1) Some mammalian ORs have exceptionally broad response spectra; i.e., they respond to a large array of diverse odorants. These ORs may serve distinct roles in odor detection and discrimination as compared to typical, narrowly-tuned ORs. (2) OSNs expressing certain OR types respond to both odorous ligands and mechanical stimuli. The mechanosensitivity of OSNs may convey the breathing information to the brain with the accompanied smells. By combining patch clamp, gene-targeting, site-directed mutagenesis, heterologous expression, viral transfection, and computational modeling approaches, this project aims to address two fundamental questions. First, what defines the tuning breadth of an OR? The hypothesis that broadly-tuned ORs require permissive binding cavity and low activation threshold (i.e., high basal activity) will be tested ad the key residues responsible for odorant binding and receptor activation will be identified. Second, what underlies mechanosensitivity of OSNs expressing certain OR types? The hypothesis that ORs with high basal activity tend to confer mechanosensitivity in the host cells will be tested. Overall, these experiments will offer critical insights into structure-function relationship of GPCRs, activation of ORs by chemical and mechanical stimulation, and information processing in the olfactory system.
G-protein coupled receptors (GPCRs) are the targets of nearly 40% of all modern therapeutic drugs. A better understanding of structure-function relationship of GPCRs will help to design drugs with higher sensitivity and specificity. In addition, millions of people suffer from smell dysfunction, which negatively impacts their quality of life. This project may facilitate development of medical treatments to enhance desired smell functions.
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