title: Soluble adenylyl cyclase mediates nerve growth factor-induced activation of Rap1.
abstract: Nerve growth factor (NGF) and the ubiquitous second messenger cyclic AMP (cAMP) are both implicated in neuronal differentiation. Multiple studies indicate 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 have described 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. These inhibitors, along with sAC-specific small interfering RNA, 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, transmembrane adenylyl cyclase-generated cAMP is responsible for Rap1 activation by the G protein-coupled receptor ligand PACAP (pituitary adenylyl cyclase-activating peptide). These results identify sAC as a mediator of NGF signaling and reveal the existence of distinct pathways leading to cAMP-dependent signal transduction.
authors.affiliation: Department of Pharmacology, New York, New York 10021; Tri-institutional M.D./Ph.D. Program, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Stessin
authors.affiliation: Department of Pharmacology, New York, New York 10021; Tri-institutional M.D./Ph.D. Program, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Zippin
authors.affiliation: Department of Pharmacology, New York, New York 10021.
authors.forename: Margarita
authors.initials: M
authors.lastname: Kamenetsky
authors.affiliation: Department of Pharmacology, New York, New York 10021.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Hess
authors.affiliation: Department of Pharmacology, New York, New York 10021. Electronic address: jobuck@med.cornell.edu.
authors.forename: Jochen
authors.initials: J
authors.lastname: Buck
authors.affiliation: Department of Pharmacology, New York, New York 10021.
authors.forename: Lonny R
authors.initials: LR
authors.lastname: Levin
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D020932:Nerve Growth Factor / Q000378:metabolism*; D016716:PC12 Cells; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D034741:RNA, Small Interfering; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins; D000262:Adenylyl Cyclases; D002118:Calcium