Mammals have the capacity to discriminate between an immense variety of odorants and pheromones. Pheromones are airborne chemical signals that are released by an individual into that affect the physiology and behavior of other members of the same species. Volatile and non-volatile compounds can both act as pheromones. Detection of odorants and pheromones is mediated through receptors in the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). Sensing of pheromones by humans has been controversial because humans apparently do not have functional VNO. However, our recent data indicating that some mouse sexual activity is dependent on signaling mechanisms in the MOE suggests the interesting possibility that humans may also detect some pheromones through the MOE. This grant focuses on signal transduction mechanisms in the MOE and main olfactory bulb (MOB) that mediate detection of pheromones in the MOE as well as the survival of newly formed granule cells in the MOB caused by pheromone or odorant exposure. It is the central hypothesis of this grant that several types of signals detected through the MOE including volatile odorants and pheromones are mediated through the type 3 adenylyl cyclase (AC3), a calcium inhibited enzyme. We hypothesize that some pheromones or volatile odorants that contribute to male sexual activity and female selection of males are detected through receptors in the MOE coupled to AC3 by the G-coupling protein Golf. We hypothesize that pheromones and odorants activate signaling pathways in the MOE that generate signals propagated through axonal projections to the MOB. We propose that this leads to activation of the MAPK/CREB pathway in the MOB and increased survival of newly formed granule cells in the MOB. We also hypothesize that odorant- and pheromone-induced activation of MAPK in the MOB depends upon the calcium-stimulated degradation of SCN Circadian Oscillatory Protein (SCOP), a negative regulator of MAPK signaling in other neurons.

Public Health Relevance

The chemosensory systems of mammals have the exquisite capacity to discriminate between an immense variety of odorants and pheromones. Perturbations of the olfactory system cause loss of appetite and poor nutrition, particularly with older patients. For example, the average human loses a significant proportion of their olfaction as they age, and olfactory dysfunction is associated with several aging-related neurodegenerative diseases including Alzheimer's and Parkinson's disease. Although controversial, there is also increasing evidence that humans may also detect some pheromones. Pheromones are "airborne chemical signals that are released by an individual into the environment that affect the physiology and behavior of other members of the same species". Volatile and non-volatile compounds can both act as pheromones. Pheromones provide information about gender and reproductive status, while also mediating social and sexual behaviors as well as neuro-endocrine changes. This grant focuses on mechanisms for detection of odorants and pheromones.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC004156-14
Application #
8277394
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Sullivan, Susan L
Project Start
1999-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
14
Fiscal Year
2012
Total Cost
$317,683
Indirect Cost
$114,040
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Zou, Junhui; Storm, Daniel R; Xia, Zhengui (2013) Conditional deletion of ERK5 MAP kinase in the nervous system impairs pheromone information processing and pheromone-evoked behaviors. PLoS One 8:e76901
Zou, Junhui; Pan, Yung-Wei; Wang, Zhenshan et al. (2012) Targeted deletion of ERK5 MAP kinase in the developing nervous system impairs development of GABAergic interneurons in the main olfactory bulb and behavioral discrimination between structurally similar odorants. J Neurosci 32:4118-32
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Wang, Zhenshan; Phan, Trongha; Storm, Daniel R (2011) The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia. J Neurosci 31:5557-61
Phan, Trongha X; Phan, Trongha H; Chan, Guy C-K et al. (2011) The diurnal oscillation of MAP (mitogen-activated protein) kinase and adenylyl cyclase activities in the hippocampus depends on the suprachiasmatic nucleus. J Neurosci 31:10640-7
Wang, Zhenshan; Storm, Daniel R (2011) Maternal behavior is impaired in female mice lacking type 3 adenylyl cyclase. Neuropsychopharmacology 36:772-81
Lim, Jae H; Davis, Greg E; Wang, Zhenshan et al. (2009) Zicam-induced damage to mouse and human nasal tissue. PLoS One 4:e7647
Wang, Zhenshan; Nudelman, Aaron; Storm, Daniel R (2007) Are pheromones detected through the main olfactory epithelium? Mol Neurobiol 35:317-23

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