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Papers In Press, published online ahead of print April 20, 2006
J. Biol. Chem, 10.1074/jbc.M603500200
Submitted on April 12, 2006
Accepted on April 20, 2006
Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021
Corresponding Author: jobuck{at}med.cornell.edu
Nerve growth factor (NGF) and the ubiquitous second messenger cyclic AMP (cAMP) are both implicated in neuronal differentiation. Multiple studies indicated that NGF signals to at least a subset of its targets via cAMP, but the link between NGF and cAMP has remained elusive. Here, we describe the use of small molecule inhibitors to differentiate between the two known sources of cAMP in mammalian cells, bicarbonate and calcium responsive soluble adenylyl cyclase (sAC) and G protein regulated transmembrane adenylyl cyclases (tmACs). These inhibitors, along with sAC-specific siRNA, reveal that sAC is uniquely responsible for the NGF-elicited rise in cAMP and is essential for the NGF-induced activation of the small G protein Rap1 in PC12 cells. In contrast and as expected, tmAC-generated cAMP is responsible for Rap1 activation by the G protein coupled receptor ligand, pituitary adenylyl cyclase activating peptide (PACAP). These results identify sAC as a mediator of NGF signaling and reveal the existence of distinct pathways leading to cAMP-dependent signal transduction.
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