Intracelluar cAMP controls aspects of carbolydrate, lipid, protein and nucleic acid metabolism in animal cells. Futhermore, cAMP plays an important role for several types of neuronal function including synaptic transmission, and the activity of specific ion channels is regulated by cAMP. The levels of cAMP in brain are directly controlled by adenylate cyclase which is regulated by neurotransmitters and Ca2+. The long-term objectives of this project are to elucidate the mechanisms for regulation of brain adenylate cyclase by Ca2+, CaM, and cAMP dependent protein kinase. Our laboratory has recently purified this enzyme to homogeneity and obtained polyclonal antibodies against the CaM sensitive adenylate cyclase front bovine brain. Furthermore, we have recently discovered a protein from brain, designated pp90, that activates brain adenylate cyclase which we suspect is a calcium binding protein.
Specific aims of this project include the purification of CaM sensitive adenylate cyclase from bovine brain using immunoaffinity chromatography, purification of the CaM sensitive adenylate cyclase from brain, examination of the CaM, Ca2+, and isoproterenol sensitivity of the CaM sensitive adenylate cyclase reconstituted with beta adrenergic receptors, and elucidation of the mechanism for regulation of the enzyme by cAMP dependent protein kinase. Furthermore, we propose to elucidate the mechanism for regulation of adenylate cyclase by pp90. We will also attempt to clone cDNA's encoding the sequence of the catalytic submit of the CaM sensitive adenylate cyclase from bovine brain. This project should provide fundemental information concerning the structure of adenylate cyclases and the mechanisms for regulation of the enzyme by Ca2+, protein kinases, and catecholamines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020498-07
Application #
3400850
Study Section
Biochemistry Study Section (BIO)
Project Start
1984-04-01
Project End
1995-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Luo, Jie; Chen, Xuanmao; Pan, Yung-Wei et al. (2015) The type 3 adenylyl cyclase is required for the survival and maturation of newly generated granule cells in the olfactory bulb. PLoS One 10:e0122057
Wang, Wenbin; Pan, Yung-Wei; Zou, Junhui et al. (2014) Genetic activation of ERK5 MAP kinase enhances adult neurogenesis and extends hippocampus-dependent long-term memory. J Neurosci 34:2130-47
Chen, Ying-Zhang; Friedman, Jennifer R; Chen, Dong-Hui et al. (2014) Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia. Ann Neurol 75:542-9
Saraf, Amit; Luo, Jie; Morris, David R et al. (2014) Phosphorylation of eukaryotic translation initiation factor 4E and eukaryotic translation initiation factor 4E-binding protein (4EBP) and their upstream signaling components undergo diurnal oscillation in the mouse hippocampus: implications for memory per J Biol Chem 289:20129-38
Wardlaw, Sarah M; Phan, Trongha X; Saraf, Amit et al. (2014) Genetic disruption of the core circadian clock impairs hippocampus-dependent memory. Learn Mem 21:417-23
Hwang, Christopher K; Chaurasia, Shyam S; Jackson, Chad R et al. (2013) Circadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells. J Neurosci 33:14989-97
Pan, Yung-Wei; Storm, Daniel R; Xia, Zhengui (2013) Role of adult neurogenesis in hippocampus-dependent memory, contextual fear extinction and remote contextual memory: new insights from ERK5 MAP kinase. Neurobiol Learn Mem 105:81-92
Luo, Jie; Phan, Trongha X; Yang, Yimei et al. (2013) Increases in cAMP, MAPK activity, and CREB phosphorylation during REM sleep: implications for REM sleep and memory consolidation. J Neurosci 33:6460-8
Chen, Xuanmao; Xia, Zhengui; Storm, Daniel R (2012) Stimulation of electro-olfactogram responses in the main olfactory epithelia by airflow depends on the type 3 adenylyl cyclase. J Neurosci 32:15769-78
Pan, Yung-Wei; Chan, Guy C K; Kuo, Chay T et al. (2012) Inhibition of adult neurogenesis by inducible and targeted deletion of ERK5 mitogen-activated protein kinase specifically in adult neurogenic regions impairs contextual fear extinction and remote fear memory. J Neurosci 32:6444-55

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