Olfactory Signal Transduction and Neuromodulation of Ion Channels
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.
Selected Recent Publications
Thiebaud N, Johnson MC, Butler JL, Bell GA, Ferguson KL, Fadool AR, Fadool JC, Gale AM, Gale DS, Fadool DA. Hyperlipidemic diet causes loss of olfactory sensory neurons, reduces olfactory discrimination, and disrupts odor-reversal learning.. J. Neurosci.. 34(20):6970-84. (2014)
Johnson MC, Biju KC, Hoffman J, Fadool DA
. Odor enrichment sculpts the abundance of olfactory bulb mitral cells.
. Neurosci Lett
. 541:173-178. (2013) PDF
Tucker K, Cho S, Thiebaud N, Henderson M, Fadool DA
. Glucose sensitivity of mouse olfactory bulb neurons is conveyed by a voltage-gated potassium channel.
. J. Physiol.
. 591(10): 2541-2561. (2013) PDF
Tucker K, Michael Overton J, Fadool DA
. Diet-induced obesity resistance of Kv1.3-/- mice is olfactory bulb dependent.
. J Neuroendocrinol.
. 24(8):1087-1095. (2012) PDF
Mast TG, Fadool DA
. Mature and precursor brain-derived neurotrophic factor have individual roles in the mouse olfactory bulb.
. PLoS One
. 7(2):e31978. (2012) PDF
[Epub 2012 Feb 21]
Palouzier-Paulignan B, Lacroix MC, Aimé P, Baly C, Caillol M, Congar P, Julliard AK, Tucker K, Fadool DA
. Olfaction Under Metabolic Influences.
. Chem Senses
. (2012) PDF
[[Epub ahead of print]]
Corthell JT, Fadool DA
, Trombley PQ. Connexin and AMPA receptor expression changes over time in the rat olfactory bulb.
. 222: 38-48. (2012) Abstract
Tucker KR, Godbey SJ, Thiebaud N, Fadool DA
. Olfactory ability and object memory in three mouse models of varying body weight, metabolic hormones, and adiposity.
. Physiol. Behav.
. 107(3): 424-432. (2012) PDF
, Tucker K, Pedarzani P. Mitral cells of the olfactory bulb perform metabolic sensing and are disrupted by obesity at the level of the Kv1.3 ion channel.
. PLoS One
. 6(9):e24921. (2011) PDF
[Epub 2011 Sep 22]
Mast TG, Brann JH, Fadool DA
. The TRPC2 channel forms protein-protein interactions with Homer and RTP in the rat vomeronasal organ
. BMC Neuroscience
. 11:61. (2010) PDF
Tucker K, Cavallin MA, Jean-Baptiste P, Biju KC, Overton JM, Pedarzani P, Fadool DA
. The Olfactory Bulb: A Metabolic Sensor of Brain Insulin and Glucose Concentrations via a Voltage-Gated Potassium Channel.
. Results Probl Cell Differ.
. 52:147-57. (2010) PDF
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
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
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