MECHANISMS OF OLFACTORY TRANSDUCTION

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DESCRIPTION: (provided by applicant) The significance of olfaction in maintaining our overall quality of life is becoming increasingly appreciated with advances in our understanding of how odors influence the enjoyment of food and beverages and our sense of well-being. Aging, disease, drugs and environmental pollutants all adversely affect the perception of odors. Odors are detected by millions of sensory neurons in the nose that generate an electrical signal in response to stimulation by particular chemicals. Recognition of odors is mediated by a large variety of receptor proteins located in the membranes of cilia projecting from the exposed ends of the receptor neurons. Odorant receptor proteins are linked by GTP-binding regulatory proteins to the formation of intracellular second messengers, which in turn modulate membrane conductance and the generation of an electrical response. Disruption of any of the steps coupling odorant binding to the generation of the electrical response would result in impairment of function. Several families of odorant receptors and many of the components of the transduction cascade have been identified by molecular cloning techniques. However, functional expression of receptors and matching a particular receptor with its cognate odorants have proven a daunting task in mammals, where there are perhaps thousand receptors and tens of thousands of odorants. Fish respond to many fewer odorants and have an order of magnitude fewer odorant receptors. We will use molecular and electrophysiological approaches to characterize olfactory transduction in a primitive vertebrate model. Sea lampreys appear to respond to only a few dozen odorants. Assuming a correspondingly restricted number of odorant receptors, the probability of matching an odorant with its receptor is greatly increased. A few amino acid odorants, as well as two pheromones, have been identified in this system, and several cDNAs encoding presumed odorant receptors have been isolated. Once full-length clones are obtained, they will be characterized by expression in heterologous systems. The results will allow elucidation of at least one complete signal transduction cascade in receptor neurons of a vertebrate, from interaction of odorant with a receptor to the generation of action potentials.