Vertebrates can recognize and discriminate thousands of odorants of diverse molecular structure. How is this process of molecular recognition accomplished? The identification of an odorant's chemical structure is thought to occur through the combinatorial integration from multiple odorant receptors, each tuned to recognize different molecular features. Thus, by elucidating the molecular specificities of the odorant receptors we will gain a better understanding how information is processed in the olfactory system. In this application, we focus on the properties of the """"""""C family"""""""" G protein-coupled receptors expressed in the vertebrate olfactory system. This receptor family includes the putative pheromone-sensing receptors of the mammalian vomeronasal system and the amino acid sensing receptor of the fish olfactory system. Our studies comprise three lines of investigation: (1) Based on the known structure of related receptors, we will perform molecular modeling and functional validation on the ligand binding pocket of a goldfish odorant receptor activated by amino acids - potent odorants for fish. Through this approach, we will identify the critical interactions between ligand and receptor that afford molecular specificity and lead to odorant receptor activation. (2) To unravel the receptor combinatorials used to encode olfactory information, we will isolate additional C family olfactory receptors from the goldfish and zebrafish and identify their cognate ligands. By characterizing the molecular specificities of a broader collection of odorant receptors, we will understand with greater clarity how multiple receptors are used in combination to recognize and discriminate odorants. (3) Recent evidence suggests that some odorant receptors can be coexpressed within the same sensory neuron. Do multiple receptors function independently within a cell, or do they form heteromeric complexes whose ligand specificities are an emerging property of the intermolecular interaction? We will determine whether members of the C family olfactory receptors form oligomeric complexes and whether aspects of receptor function - including ligand specificity, signal transduction, and intracellular trafficking - are altered in hetero-oligomeric complexes. These studies will help establish what role, if any, receptor oligomerization plays in determining and diversifying the response specificity of the olfactory sensory neuron. Together our studies will help to elucidate the molecular and cellular mechanisms of olfactory coding.
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