The proposed research presents a novel concept that provides a uniform signaling theme in sensory neurons. The central component of this theme is the ROS-GC transduction machinery. The machinery is operated by the fluxes in free Ca2+ arising inside the cellular compartment of the neuron. Each flux is sensed by a Ca2+ sensor component of the machinery, termed the transducer. The transducer then accelerates or inhibits the operational activity of the machinery. Acceleration causes an increment, and inhibition causes a decrement in the production of the second messenger cyclic GMP. It is then predicted that cyclic GMP, via a cyclic GMP-gated channel, regulates the degree of polarization of the sensory neuron. Specificity in acceleration or inhibition of the machinery resides in the nature of the transducer, of which there are two types-one type inhibiting and the other stimulating ROS-GC activity. Both transducer types belong to a family of Ca2+-binding proteins. GCAPs represent the inhibitory and CD-GCAPs the stimulatory type of the transducers. There are two forms of GCAPs:GCAP1 and GCAP2, and two of CD-GCAPs: S100beta and neurocalcin. Each subtype of the transducer exhibits its biological activity through the specified domain in ROS-GC with which it binds, and then either stimulates or inhibits the catalytic cyclase activity. ROS-GC exists in three forms: ROS-GC1, ROS-GC2 and ONE-GC. In this manner, composition of the ROS-GC transduction machinery defines its functional status and cellular specificity. Consistent with the proposed neurosignaling concept, the presented evidence shows that the ROS-GC transduction machinery exists in the sensory neurons of photoreceptors, olfaction, pinealocytes, and SCN. But its composition varies from cell to cell. The proposed Specific Aims are designed to test the """"""""ROS-GC Transduction"""""""" concept in the model system of olfactory neurons. This system is composed of three distinct neuronal regions: 1) the olfactory neuroepithelium, 2) the olfactory bulb, and 3) the olfactory cortex. These neuronal regions will be analyzed at a physiological, biochemical, functional, and immunological level for the presence and composition of the ROS-GC transduction system; and a determination of the functional motif of each of the ROS-GCs for its transducer present in each of the respective region will be made. Through the years, a series of comprehensive immunological, genetic, biochemical and cell-specific probes have been developed against a variety of epitopes of the ROS-GC signal transduction components. These, and other soon to be developed tools, will be used to accomplish the specified aims. Although the proposed research is of a most fundamental nature, its biochemical ramifications in understanding the basic principles associated with the sensory perception of smell, vision, taste, and biological rhythms are numerous. it is envisioned that this knowledge will ultimately be applied in rectifying the pathologies associated with these neurosensory processes.
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