There is increasing evidence that the cAMP signal transduction system plays key neuromodulatory roles in the central nervous system of vertebrates. Furthermore, cross-talk between signal transduction systems may be particularly important for adaptive changes in neurons and at synapses. Coupling of the Ca2+ and cAMP regulatory systems by the calmodulin regulated adenylyl cyclases is thought to be important for some forms of synaptic plasticity, neuroendocrine function, and sensory detection. In contrast to type I and type 8 adenylyl cyclases, which are stimulated by Ca2+, type 3 adenylyl cyclase (AC3) is strongly activated by Gs-coupled receptors and inhibited by Ca2+. Ca2+ inhibition of AC3 is mediated by CaM kinase II which directly phosphorylates AC3 at Ser-1076 in vivo. This proposal focuses around the hypothesis that the unique regulator properties of AC3 may contribute to cAMP transients observed in some neurons. Since odorant-induced cAMP increases are rapidly followed by elevated intracellular Ca2+, Ca2+ inhibition of AC3 may play a pivotal role in attenuation of cAMP signals caused by odorants. We propose to evaluate this hypothesis using several unique tools developed in this laboratory including AC3 mutant transgenic mice and a peptide-specific antibody for the CaM kinase II phosphorylation site within AC3. This study should provide fundamental information concerning the role of AC3 and CaM kinase II for generation of cAMP transients in neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
1R01DC004156-01
Application #
2881770
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Project Start
1999-08-01
Project End
2004-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Chen, Xuanmao; Luo, Jie; Leng, Yihua et al. (2016) Ablation of Type III Adenylyl Cyclase in Mice Causes Reduced Neuronal Activity, Altered Sleep Pattern, and Depression-like Phenotypes. Biol Psychiatry 80:836-848
Cao, Hong; Chen, Xuanmao; Yang, Yimei et al. (2016) Disruption of type 3 adenylyl cyclase expression in the hypothalamus leads to obesity. Integr Obes Diabetes 2:225-228
Stratigopoulos, George; Burnett, Lisa Cole; Rausch, Richard et al. (2016) Hypomorphism of Fto and Rpgrip1l causes obesity in mice. J Clin Invest 126:1897-910
Wang, Wenbin; Lu, Song; Li, Tan et al. (2015) Inducible activation of ERK5 MAP kinase enhances adult neurogenesis in the olfactory bulb and improves olfactory function. J Neurosci 35:7833-49
Chen, Xuanmao; Cao, Hong; Saraf, Amit et al. (2015) Overexpression of the type 1 adenylyl cyclase in the forebrain leads to deficits of behavioral inhibition. J Neurosci 35:339-51
Liu, Jack J; Chan, Guy C; Hecht, Avi S et al. (2014) Nasal saline irrigation has no effect on normal olfaction: a prospective randomized trial. Int Forum Allergy Rhinol 4:39-42
Liu, Jack J; Chan, Guy C; Hecht, Avram S et al. (2014) Comparison of two nasal cell collection methods in determining cyclic adenosine monophosphate levels and its association with olfaction: A feasibility study. Allergy Rhinol (Providence) 5:17-21
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
Li, Tan; Pan, Yung-Wei; Wang, Wenbin et al. (2013) Targeted deletion of the ERK5 MAP kinase impairs neuronal differentiation, migration, and survival during adult neurogenesis in the olfactory bulb. PLoS One 8:e61948
Chen, Xuanmao; Xia, Zhengui; Storm, Daniel R (2013) Electroolfactogram (EOG) Recording in the Mouse Main Olfactory Epithelium. Bio Protoc 3:

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