Functional domains and expression of olfactory receptors. The family of olfactory receptors determines the specificity of activation of olfactory receptor neurons, thereby defining the neural coding of every odor perception. This proposal describes studies of functional molecular domains of olfactory receptor proteins. The first objective is to determine the specificity of G-protein interactions of two or more olfactory receptors. These experiments will test hypotheses about the location of the domains which interact with G-proteins, their structures, the amino acids which determine coupling in these domains, the spatial relationships between the domains and between the important amino acids. Preliminary data from olfactory/beta2-adrenergic receptor chimeras predIct that olfactory receptors are capable of interacting with the G-proteins of heterologous cells and that olfactory receptors cause the production of cAMP. These functional expression experiments are performed in a novel assay system which uses optical methods (video imaging and microplate reader) to detect the second messenger-activated movement of pigment organelles in melanophore cell lines. This assay system is capable of efficiently screening thousands of odorants against dozens of olfactory receptor clones to determine odor-response spectra. These spectra are crucial to understanding the neural coding of odor stimuli. Preliminary data show that olfactory receptors are poorly expressed in the plasma membrane of melanophores. These findings may explain the lack of progress in functional expression studies using a variety of heterologous cell types. The second objective is therefore to investigate the molecular basis for the inability of olfactory receptors to be expressed in the plasma membrane of melanophores. The hypotheses to be tested are that olfactory receptors possess an internal sorting or folding signal that is misinterpreted by heterologous cells and that an olfactory-specific accessory protein is necessary for the proper expression of olfactory receptors. This proposal represents a systematic approach toward understanding the odorant and G-protein specificity of a large number of olfactory receptors. As such, this project will have direct implications for our understanding of anosmias and their impact upon the quality of human life.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
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Sensory Disorders and Language Study Section (CMS)
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University of Kentucky
Schools of Medicine
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Zhang, Guangfan; Titlow, William B; Biecker, Stephanie M et al. (2016) Lhx2 Determines Odorant Receptor Expression Frequency in Mature Olfactory Sensory Neurons. eNeuro 3:
McClintock, Timothy S (2015) Odorant Receptor Gene Choice. ChemoSense 16:3-13
McClintock, Timothy S; Adipietro, Kaylin; Titlow, William B et al. (2014) In vivo identification of eugenol-responsive and muscone-responsive mouse odorant receptors. J Neurosci 34:15669-78
Fischl, Adrian M; Heron, Paula M; Stromberg, Arnold J et al. (2014) Activity-dependent genes in mouse olfactory sensory neurons. Chem Senses 39:439-49
Nickell, Melissa D; Breheny, Patrick; Stromberg, Arnold J et al. (2012) Genomics of mature and immature olfactory sensory neurons. J Comp Neurol 520:2608-29
Sammeta, Neeraja; Hardin, Debra L; McClintock, Timothy S (2010) Uncx regulates proliferation of neural progenitor cells and neuronal survival in the olfactory epithelium. Mol Cell Neurosci 45:398-407
McClintock, Timothy S (2010) Achieving singularity in mammalian odorant receptor gene choice. Chem Senses 35:447-57
McIntyre, Jeremy C; Titlow, William B; McClintock, Timothy S (2010) Axon growth and guidance genes identify nascent, immature, and mature olfactory sensory neurons. J Neurosci Res 88:3243-56
Sammeta, Neeraja; McClintock, Timothy S (2010) Chemical stress induces the unfolded protein response in olfactory sensory neurons. J Comp Neurol 518:1825-36
McClintock, Timothy S; Glasser, Chad E; Bose, Soma C et al. (2008) Tissue expression patterns identify mouse cilia genes. Physiol Genomics 32:198-206

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