Soluble adenylyl cyclase mediates nerve growth factor-induced activation of Rap1

被引:64
|
作者
Stessin, Alexander M.
Zippin, Jonathan H.
Kamenetsky, Margarita
Hess, Kenneth C.
Buck, Jochen
Levin, Lonny R.
机构
[1] Cornell Univ, Weill Med Coll, Dept Pharmacol, New York, NY 10021 USA
[2] Cornell Univ, Weill Med Coll, Tri Inst MD PhD Program, New York, NY 10021 USA
关键词
D O I
10.1074/jbc.M603500200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:17253 / 17258
页数:6
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