Recent evidence has uncovered unexpected functions for a particular Shaker family member, Kv1.3, through gene-targeted deletion approaches. Using whole-cell electrophysiology, we have previously demonstrated that the Kv1.3 current component of mitral cells in the olfactory bulb is modulated by insulin receptor kinase and neurotrophin TrkB, two receptor tyrosine kinase (RTKs) pathways. Upon deletion of the Kv1.3 channel, the expression of the RTKs and their associated scaffolding proteins was perturbed as determined by SDS-PAGE and the mitral cells were insensitive to insulin and BDNF, the preferred ligands for these RTKs. The action potential frequency, 10 to 90% rise time, afterhyperpolarization, and duration was significantly changed in mitral cells of the Kv1.3-null animals. In light of these marked electrical and biochemical changes in neuronal signaling in the olfactory bulb, we were intrigued to explore the ability of the mice to smell. Contrary to our expectation, mice were not anosmic when tested for simple metrics of olfactory ability that did not require learning or memory. In fact, using odorant habituation paradigms, Kv1.3-null mice had the capacity to discriminate odorant molecules that differed by one to four carbon atoms and when challenged with a memory-based, two-choice paradigm, Kv1.3-null mice were found to have significantly different odorant thresholds; detecting odorants that were 10,000 to 100,000 x lower in concentration than those of wildtype animals. Mice were also monitored in environmental metabolic chambers designed for continuous determination of oxygen consumption, locomotor activity, and ingestive behaviors. The body weight of Kv1.3-null mice was less than that of the wildtype mice even though total caloric and water intake was not different. To test whether deletion of the Kv1.3 gene could prevent weight gain, we bred Kv1.3-null animals with mice lacking the melocortin receptor gene (MC4R) that is found to be defective in human obesity. MC4R mice are hyperphagic and have a late-onset weight gain typical of type 2 diabetes. Progeny were initially solely monitored for weight gain (early developmental and adult late onset) for 1 yr. Mice with the double allelic combination (mmkk) were not significantly different in weight than that of the control wildtype (MMKK) while the MC4R-null mice (mmKK) gained significant weight at 2 months that continued to rise throughout adulthood, suggesting that the deletion of the Kv1.3 gene can prevent weight gain (ANOVA, snk, n = 36). Currently we are testing 3 of the allelic combinations (mmkk, MMKK, and mmKK) with a battery of mouse behavioural and cellular phenotypic screens. In our analysis we hope to characterize the degree to which obesity affects olfactory signaling and the role in which Kv1.3 ion channel mediates energy homeostasis. Due to the combined increased olfactory ability of the Kv1.3-null mice and altered electrical signaling of the mitral cell neurons, we explored the potential anatomical changes in the olfactory bulb of the null mice to find that the mean size of the glomeruli were both significantly smaller and more numerous. We thus tested the hypothesis that axonal projections were altered in the Kv1.3-null mice by crossing them with two different lines of mice in which a single odorant receptor (called M72 or P2) is linked to the expression of lacZ-tagged tau protein. We conjectured that neurotrophins (a 7x increase by SDS-PAGE) may be differentially regulating axonal growth in the absence of the ion channel thereby allowing projections to more than one glomeruli. Visualization of the axonal projections from olfactory sensory neurons (OSNs) containing the P2 receptor protein did not reveal any obvious differences in the location and single glomerular projection between the wildtype and the Kv1.3-null animals. For OSNs containing the M72 receptor protein, however, axons typically projected to three glomeruli as opposed to a single glomerulus in the Kv1.3-null animals and the total number of OSNs expressing M72 receptor protein was significantly reduced. Although the pattern of OSN expression of M72 receptor protein in the olfactory epithelium was not altered, that of the P2 receptor protein was located in the most ventral region of the olfactory epithelium in the null-mice as opposed to its typically dorsal region of expression in wildtype mice. These data suggest that the Kv1.3 channel plays a far more reaching role than that classically defined for a potassium channel – to shape excitability by influencing the membrane potential – and may have important regulatory roles for olfactory sensory processing, protein-protein interactions, olfactory coding and axonal targeting, and energy homeostasis.