title: Phosphoinositide and Erk signaling pathways mediate activity-driven rodent olfactory sensory neuronal survival and stress mitigation.
abstract: Olfactory sensory neurons (OSNs) are the initial site for olfactory signal transduction. Therefore, their survival is essential to olfactory function. In the current study, we demonstrated that while odorant stimulation promoted rodent OSN survival, it induced generation of reactive oxygen species in a dose- and time-dependent manner as well as loss of membrane potential and fragmentation of mitochondria. The MEK-Erk pathway played a critical role in mediating these events, as its inhibition decreased odorant stimulation-dependent OSN survival and exacerbated intracellular stress measured by reactive oxygen species generation and heat-shock protein 70 expression. The phosphoinositide pathway, rather than the cyclic AMP pathway, mediated the odorant-induced activation of the MEK-Erk pathway. These findings provide important insights into the mechanisms of activity-driven OSN survival, the role of the phosphoinositide pathway in odorant signaling, and demonstrate that odorant detection and odorant stimulation-mediated survival proceed via independent signaling pathways. This mechanism, which permits independent regulation of odorant detection from survival signaling, may be advantageous if not diminished by repeated or prolonged odor exposure. We investigated the role of odorant stimulation in generating cellular stress and the molecular mechanisms mitigating such stress and promoting neuronal survival. Odorant stimulation promoted olfactory sensory neuron (OSN) survival and also induced intracellular oxidative stress, which was exacerbated when MEK/Erks pathway was inhibited. Sensory stimulation simultaneously activated at least two parallel pathways, the AC/cAMP cascade responsible for odorant detection, and phosphoinositide hydrolysis to promote odorant stimulation-dependent neuronal survival odorants may activate parallel signaling cascades to mediate sensory detection and sensory stimulation-dependent survival. AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; Erk, extracellular signal-regulated kinase; MEK, MAPK/ERK kinase.
authors.affiliation: Department of Brain & Cognitive Sciences, Graduate School, DaeguGyeungbuk Institute of Science and Technology, Daegu, Korea.
authors.forename: So Yeun
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Departments of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Mammen
authors.affiliation: Department of Brain & Cognitive Sciences, Graduate School, DaeguGyeungbuk Institute of Science and Technology, Daegu, Korea.
authors.forename: Seung-Jun
authors.initials: SJ
authors.lastname: Yoo
authors.affiliation: Department of Brain & Cognitive Sciences, Graduate School, DaeguGyeungbuk Institute of Science and Technology, Daegu, Korea.
authors.forename: Bongki
authors.initials: B
authors.lastname: Cho
authors.affiliation: Department of Brain & Cognitive Sciences, Graduate School, DaeguGyeungbuk Institute of Science and Technology, Daegu, Korea.
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Jong-In
authors.initials: JI
authors.lastname: Park
authors.affiliation: Department of Brain & Cognitive Sciences, Graduate School, DaeguGyeungbuk Institute of Science and Technology, Daegu, Korea.
authors.forename: Cheil
authors.initials: C
authors.lastname: Moon
authors.affiliation: Department of Brain & Cognitive Sciences, Graduate School, DaeguGyeungbuk Institute of Science and Technology, Daegu, Korea.|Departments of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Gabriele V
authors.initials: GV
authors.lastname: Ronnett
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002470:Cell Survival; D015151:Immunoblotting; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018034:Olfactory Receptor Neurons / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010716:Phosphatidylinositols / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012903:Smell / Q000502:physiology
chemical_list: D010716:Phosphatidylinositols
keywords: activity-driven survival; mitogen-activated protein kinase; olfactory; oxidative stress; phosphoinositide; sensory transduction