Research Interest
Olfactory Signal Transduction and Neuromodulation of Ion Channels
Current Projects
We are researching learning, memory, and neural plasticity at the level of the ion channel protein. Our main stay in the laboratory is biophysics, specifically a technique called patch-clamp electrophysiology, where we can measure single conformational changes in ion channel proteins that elicit electrical signals, essentially the language of the brain. One of the most ubiquitous ways of modulating electrical activity of ion channels is a biochemical process called phosphorylation, whereby negative phosphate groups are added to the channel at specific residues. Hence we combine our skills in electrophysiology with those of protein biochemistry (phosphorylation assays; protein-protein interactions), molecular biology (creating mutant ion channels and signaling proteins), and molecular genetics (genetically targeted "knock-out" mice to study cell signaling by loss of function). We were very much excited that the 2000 Nobel Prize in Physiology or Medicine was attributed to several scientists that discovered the importance of phosphorylation. Perhaps the importance of phosphorylation in regulating cellular activity can be underscored by the large portion (2-3%) of the eukaryotic genome set aside to code for kinases, enzymes that initiate phosphorylation. Humans have 2000 conventional kinase genes and most of those exist in the brain. Abnormality in these genes and correlate enzyme activity could contribute to the onset or severity of specific neuronal diseases such as Alzheimer's functional, inflammatory responses, deregulated cell proliferation, and to diseases such as cancer (especially mammary), atherosclerosis, psoriasis, and diabetes. Most recently we have discovered that hormones and neurotrophins (insulin and brain-derived neurotrophic factor (BDNF)) modulate electrical activity in the brain at the level of the ion channel. Thus we are studying the neuropathology of diabetes and nerve damage through disease or injury. Since perfusion of BDNF induces new nerve cell growth, it may have this capacity by acting at the level of the ion channel.
I would welcome students wishing to gain experience with the techniques of electrophysiology (patch-clamp recording and single channel analysis), protein biochemistry, molecular biology (site-directed mutagenesis, gene-targeted deletions, 2 hybrid yeast, microarray), and immunochemistry, and to those wishing to answer questions about the physiology of olfaction, cell-signaling cascades, the regulation of neuronal excitability, and ion channel structure/function.
Publications
- Marks DR, Tucker K, Cavallin MA, Mast TG, Fadool DA. Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J Neurosci. 29(20):6734-51. (2009) PDF | Abstract
- Colley BS, Cavallin MA, Biju K, Marks DR, Fadool DA. Brain-derived neurotrophic factor modulation of Kv1.3 channel is disregulated by adaptor proteins Grb10 and nShc. BMC Neurosci. 10:8. (2009) PDF | Abstract
- Biju KC, Mast TG, Fadool DA. Olfactory sensory deprivation increases the number of proBDNF-immunoreactive mitral cells in the olfactory bulb of mice. Neurosci Lett. 447(1):42-7. (2008) PDF | Abstract
- Tucker K, Overton JM, Fadool DA. Kv1.3 gene-targeted deletion alters longevity and reduces adiposity by increasing locomotion and metabolism in melanocortin-4 receptor-null mice. Int J Obesity. 32(8): 1222-123. (2008) PDF
- Biju KC, Marks DR, Mast TG, Fadool DA. Deletion of voltage-gated channel affects glomerular refinement and odor receptor expression in the olfactory system. J Comp Neurol. 506: 161-179. (2008) PDF | Abstract
- Marks DR, Fadool DA. Post-synaptic density 95 (PSD-95) affects insulin-induced Kv1.3 channel modulation of the olfactory bulb. J Neurochem. 103(4): 1608-16. (2007) PDF | Abstract
- Colley BS, Biju KC, Visegrady A, Campbell S, Fadool DA. TrkB increases Kv1.3 ion channel half-life and surface expression. Neuroscience. 144(2):531-46. (2007) Abstract
- Brann JH, Fadool DA. Vomeronasal sensory neurons (VSNs) from Sternotherus odoratus (Stinkpot/Musk Turtle) respond to chemosignals via the phospholipase C (PLC) system. J Exp Biol. 209: 914-927. (2006)
- Das P, Parsons AD, Scarborough J, Hoffman J, Wilson J, Thompson RN, Overton JM, Fadool DA. Electrophysiological and behavioral phenotype of insulin receptor defective mice. Physiol Behav. 86(3):287-96. (2005)
- Fadool DA, Tucker K, Perkins R, Fasciani G, Thompson RN, Parsons AD, Overton JM, Koni PA, Flavell RA, Kaczmarek LK. Kv1.3 channel gene-targeted deletion produces "super-smeller mice" with altered glomeruli, interacting scaffolding proteins, and biophysics. Neuron. 41(3): 389-404. (2004)