In neurons, the ubiquitous second messenger cyclic AMP (cAMP) has been implicated in a number of growth factor signaling pathways. For example, neurotrophins, such as Nerve Growth Factor (NGF), are linked via cAMP to neuronal differentiation, neuritogenesis, and axonal regeneration. However, it has remained unclear how to link the growth factors, or their receptors, to cAMP changes. Axonal guidance cues, such as netrin-1, also signal via cAMP, and their link to second messenger generation is similarly unclear. Previously, the only known source of cAMP had been the family of G protein regulated, transmembrane adenylyl cyclases (tmACs);tmACs mediate the cAMP changes in response to neurotransmitters which act via G protein coupled, seven transmembrane spanning receptors. But all attempts to link tmACs to neuronal growth factor signals or axonal guidance cues have failed, or at best proven controversial. Our laboratory characterized a distinct source of cAMP in mammalian cells, 'soluble'adenylyl cyclase (sAC). In contrast to tmACs, sAC is not modulated by heterotrimeric G proteins but is, instead, regulated by bicarbonate and calcium ions. In preliminary results for this application, we demonstrate that sAC is responsible for cAMP generation in response to both the neurotrophin NGF and the axonal guidance cue netrin-1. We have identified a number of brain isoforms of sAC which differ from the previously cloned isoforms, and in this grant application, we propose to characterize these novel brain sAC proteins. We also propose experiments to elucidate the mechanism of sAC activation in response to NGF and netrin-1 and to determine whether this signaling cascade is utilized by other neurotrophins and in other neuronal responses. The hypotheses tested in this grant application will reveal how growth signals and guidance cues relay their information into neuronal activity. These studies have important implications for brain development, degenerative diseases and learning and memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055255-03
Application #
7535181
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
2007-02-01
Project End
2010-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
3
Fiscal Year
2009
Total Cost
$367,500
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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Ramos-Espiritu, Lavoisier S; Hess, Kenneth C; Buck, Jochen et al. (2011) The soluble guanylyl cyclase activator YC-1 increases intracellular cGMP and cAMP via independent mechanisms in INS-1E cells. J Pharmacol Exp Ther 338:925-31
Acin-Perez, Rebeca; Russwurm, Michael; Günnewig, Kathrin et al. (2011) A phosphodiesterase 2A isoform localized to mitochondria regulates respiration. J Biol Chem 286:30423-32
Buck, Jochen; Levin, Lonny R (2011) Physiological sensing of carbon dioxide/bicarbonate/pH via cyclic nucleotide signaling. Sensors (Basel) 11:2112-28

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