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J. Biol. Chem., Vol. 281, Issue 25, 17253-17258, June 23, 2006

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Soluble Adenylyl Cyclase Mediates Nerve Growth Factor-induced Activation of Rap1^*

Alexander M. Stessin, Jonathan H. Zippin, Margarita Kamenetsky, Kenneth C. Hess, Jochen Buck¹, and Lonny R. Levin

From the Department of Pharmacology, and Tri-institutional M.D./Ph.D. Program, Weill Medical College of Cornell University, New York, New York 10021

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.

Received for publication, April 12, 2006

^* This work was supported by Medical Scientist Training Program funding (to A. M. S. and J. H. Z.), National Institutes of Health Grants HD42060 and GM62328, the Ellison Medical Foundation (to J. B.), National Institutes of Health Grants HD38722 and AI64842, American Diabetes Association, and the Hirschl Weil-Caulier Trust (to L. R. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021. Tel.: 212-746-6247; Fax: 212-746-6241; E-mail: jobuck{at}med.cornell.edu.

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