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Visual and Olfactory Sensory Transductions

      The interest of our laboratory lies in the area of sensory transduction: specifically visual and olfactory transductions, which have interesting similarities but also striking differences. Visual transduction in retinal photoreceptors (the rods and cones) is known to involve a cGMP signaling pathway. In darkness, the cyclic nucleotide guanosine 3',5'-cyclic monophosphate (cGMP), a widely occurring intracellular messenger, directly activates a special cation channel on the photoreceptor and maintains a steady electrical current across the cell membrane. Absorption of light by the visual pigment rhodopsin leads to a G protein-coupled pathway that activates a phosphodiesterase to hydrolyze cGMP. As a result, the cGMP-gated channel closes, stopping the dark electrical current and producing a change in electrical potential across the cell membrane. This electrical signal is then transmitted to higher-order neurones in the retina, through modulation of neurotransmitter release from the photoreceptor synaptic terminal. Calcium ions, another ubiquitous intracellular messenger, also have an important role in phototransduction by mediating negative feedback control on the cGMP metabolism. This feedback brings about light adaptation, a crucial property of the visual system. We are currently recording from single, dissociated photoreceptors isolated from genetically modified mice and frogs, in order to address specific questions about the details of the phototransduction process. At the same time, we are expressing the cGMP-gated channel in a heterologous system and carrying out structure-function studies of this channel. Finally, we are addressing more global mechanistic and evolutionary questions about phototransduction by extending our studies to extraocular photoreceptors such as those found in the parietal eye and the pineal gland.

     Olfactory transduction likewise involves a cyclic nucleotide signaling pathway, except that in this case cAMP is the second messenger and its concentration increases in the receptor cell in response to odorant stimulation. Unlike vision, which involves only a few visual pigments in rods and cones, olfaction apparently involves of the order of a thousand distinct odorant receptor proteins. The final step of the signaling pathway is again a cyclic nucleotide-gated cation channel, which in this case opens in response to odorant stimulation due to the rise in cAMP. A key, still largely unknown question about olfactory transduction is how a given odorant receptor protein recognizes a specific set of chemicals (odorants). We are addressing this question by expressing cloned odorant receptor proteins in a heterologous system and stimulating them with various odorants, using the calcium signal (calcium imaging) as an assay. We are also developing clonal lines of olfactory receptor neurons in order to address functional and developmental questions about these cells. Finally, we are studying the olfactory cyclic nucleotide-gated channel to compare and contrast with the related channel on photoreceptors.