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Short Research Description
Cellular mechanisms of signal transduction and olfaction.
Full Research Description
The activity of all cells in the nervous system is regulated by the interaction of various chemicals, such as neurotransmitters, hormones, and peptides with membrane receptors. The ways in which these substances exert their influence is known generally as signal transduction. We use the vertebrate olfactory receptor neuron as a model for investigating general principles and mechanisms of signal transduction - receptor-ligand interactions, modulation by second messeng ers, ion channel gating, and the long term mechanisms of adaptation and desensitization. The olfactory neuron is uniquely suited for these studies since it is designed specifically for the detection and discrimination of a wide variety of small organic mo lecules, i.e. odors.
The most recent work in the lab utilizes Adenovirus vectors to drive over-expression of cloned odor receptors in olfacotry neurons. Because odor receptors make up the largest family of G-protein coupled receptors (also including many neurotransmi tter ands hormone receptors) they are excellent receptors to try and understand the relation between amino acid sequence and ligand binding affinities. We are able to overexpress particular receptors as well as receptor clones with targeted mutsations and then screen these for specific ligand sensitivities. These data are then included in computer models of the protein receptor to understand precisely why one receptor is able to recognize the odor of say, roses, while another is specific for pizza.
In another vein, olfactory receptors are unique among neurons for the ability to regenerate throughout an animal's life. Several experimental manipulations have been developed to induce neuronal regeneration and proliferation in vivo , a llowing one to harvest neurons with a known date of birth. By applying physiological techniques for cell recording we are quantifying biophysical parameters, such as the appearance of ion channels or receptors and the development of synaptic contacts, in developing neurons.
Multiple approaches are brought to bear on these questions including electrophsyiological (from patch clamp to field potential recording techniques); molecular biological, immunohistochemica l and anatomical techniques and tools.
- Otaki, J. M., and Firestein, S. (2001) Length analyses of mammalian g-protein-coupled receptors J Theor Biol 211: 77-100.
- Araneda R. C., Kini A. D., Firestein, S. (2000) The molecular receptive range of an odorant receptor Nature Neuroscience 3 (12): 1248-1255.
- Zhao, H., Ivic, L., Otaki, J., Hshimoto, M., and Firestein, S. (1998) Functional Expression of a Mammalian Odorant Receptor Science 279: 237-242.
- Menini, A., Picco, C. and Firestein, S. (1995) Quantal-like current fluctuations induced by odorants in olfactory receptor cells Nature 373: 435-437.