Olfactory receptor neurons (ORNs) have been assigned the incredible task of distinguishing between over 10,000 odor molecules. Not only must ORNs decipher the quality of odors, they must also provide the brain with intensity information. Recent studies have made considerable progress in identifying and characterizing the components of signal transduction machinery in ORNs. Odors binding to receptor proteins on olfactory cilia initiate a G-protein-mediated second messenger cascade that results in the transient elevation of cAMP or IP3. Both second messengers gate specific ion channels in the ciliary membrane, resulting in the generation of receptor potentials. Olfactory mucus provides the perireceptor environment in which the initial steps of the transduction of a chemical odor signal to an electrical receptor potential occur. Extrinsic autonomic and trigeminal innervation controls mucus secretion and may release neurotransmitters into the mucus. The presence of antioxidant chemicals in the mucus suggests that the mucus environment is permissive for neurotransmitter persistence yet the actions of those neurotransmitters are unclear. The sensitivity of ORNs to cAMP-generating odors is determined by both the sensitivity of the receptor proteins and the sensitivity of the cyclic nucleotide gated (CNG) channel. One possible role for neurotransmitters released into olfactory mucus is to modulate ORNs odor sensitivity. Potential sites for modulation include the receptor proteins, transduction cascades, and effector channels. The work in this proposal will test the hypotheses that the neurotransmitter dopamine is present in olfactory mucus, acts on D2 dopamine receptors on ORN dendrites and modulates the sensitivity of the system by changing basal levels of cAMP production. Our model suggest that the presence of dopamine in the mucus is under autonomic control and that increases or decreases in dopamine would increase or decrease the sensitivity of ORNs. This model fits with observations that stimulation of the trigeminal system decreases odor sensitivity in frogs, and that the psychophysical perception of odor intensity decreases after exposure to noxious substances (trigeminal stimuli). These studies may be clinically relevant to diseases where dopaminergic pathways are disturbed (Parkinson's) and which display decreased olfactory sensitivity as an early symptom. The work in this proposal will determine the modulatory role of dopamine on ORNs and will provide insights into how peripheral dopaminergic pathways may be involved in disease-related reduced olfactory sensitivity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
3R01DC002994-03S1
Application #
6019784
Study Section
Sensory Disorders and Language Study Section (CMS)
Project Start
1996-07-01
Project End
2001-06-30
Budget Start
1999-01-01
Budget End
1999-06-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Utah
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Ying, Guoxin; Avasthi, Prachee; Irwin, Mavis et al. (2014) Centrin 2 is required for mouse olfactory ciliary trafficking and development of ependymal cilia planar polarity. J Neurosci 34:6377-88
Lucero, Mary T (2013) Peripheral modulation of smell: fact or fiction? Semin Cell Dev Biol 24:58-70
Saund, Ranajeet S; Kanai-Azuma, Masami; Kanai, Yoshiakira et al. (2012) Gut endoderm is involved in the transfer of left-right asymmetry from the node to the lateral plate mesoderm in the mouse embryo. Development 139:2426-35
Doucette, Wilder; Gire, David H; Whitesell, Jennifer et al. (2011) Associative cortex features in the first olfactory brain relay station. Neuron 69:1176-87
Kanekar, Shami; Gandham, Mahendra; Lucero, Mary T (2010) PACAP protects against TNF?-induced cell death in olfactory epithelium and olfactory placodal cell lines. Mol Cell Neurosci 45:345-54
Hegg, Colleen Cosgrove; Irwin, Mavis; Lucero, Mary T (2009) Calcium store-mediated signaling in sustentacular cells of the mouse olfactory epithelium. Glia 57:634-44
Han, P; Lucero, M T (2006) Pituitary adenylate cyclase activating polypeptide reduces expression of Kv1.4 and Kv4.2 subunits underlying A-type K(+) current in adult mouse olfactory neuroepithelia. Neuroscience 138:411-9
Vogalis, Fivos; Hegg, Colleen C; Lucero, Mary T (2005) Electrical coupling in sustentacular cells of the mouse olfactory epithelium. J Neurophysiol 94:1001-12
Han, P; Lucero, M T (2005) Pituitary adenylate cyclase activating polypeptide reduces A-type K+ currents and caspase activity in cultured adult mouse olfactory neurons. Neuroscience 134:745-56
Vogalis, Fivos; Hegg, Colleen C; Lucero, Mary T (2005) Ionic conductances in sustentacular cells of the mouse olfactory epithelium. J Physiol 562:785-99

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