DESCRIPTION (provided by applicant): The designed research is a multidisciplinary analysis of the modulation of potassium currents in granule and mitral cells of the olfactory bulb. The broad, long-term objective of this research is to elucidate how neurotrophins and growth factors can utilize ion channels as substrates for phosphorylation to give rise to short-term and long-term plastic changes in synaptic efficacy or to aid in the establishment of neural circuits in the olfactory bulb. Understanding the general principles governing these transduction cascades and the involvement of ion channels will provide information of how protein kinases and protein phosphatases contribute to the onset or severity of specific neuronal diseases, such as Alzheimer's, or how uncontrolled signaling of these enzymes leads to deregulated cell proliferation and diseases such as cancer and diabetes. Because of the unique trophic and regenerative capacity of neurons in the olfactory system, continual expression of neuromodulators could alter patterns of electrical excitability in addition to their well-studied roles in growth and differentiation. The specific aims of this proposal are to characterize using patch-clamp electrophysiology how receptor-linked tyrosine phosphorylation signaling in the olfactory bulb is altered by sensory experience, patterned electrical stimulation, and trophic factor infusion. By utilizing the cloned, olfactory bulb potassium channel Kv1.3 as a parallel model, combined biochemical measurement of kinase-induced tyrosine phosphorylation, co-immunoprecipitation, and molecular mutagenesis will elucidate the mechanistic details of how ion channels form molecular scaffolds with kinases and adaptor proteins through discrete protein-protein interactions at SH2, SH3, PDZ, and PTB domains. Gene-targeted deletions in Kv1.3 channel, insulin receptor kinase, and TrkB kinase will provide mechanistic details for the role for tyrosine phosphorylation signaling in olfaction and for neuromodulation in the CNS in general, as defined by loss of function experiments (behavioral, biochemical, electrophysiological) using knock-out mice strains. The proposal will provide new important information regarding the integration of signaling molecules by construction of protein-protein interactions with ion channels. Modulation of ion channel function would thus be dependent upon the repertoire of signaling proteins expressed in a given neuron, a background that could change with sensory experience or electrical patterning.