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The Journal of Neuroscience, June 1, 2003, 23(11):4420-4427

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Brain-Derived Neurotrophic Factor Protection of Cortical Neurons from Serum Withdrawal-Induced Apoptosis Is Inhibited by cAMP

Steven Poser,¹ Soren Impey,¹ Zhengui Xia,^1,2 and Daniel R. Storm¹

¹ Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, and ² Department of Environmental Health and Toxicology, University of Washington, Seattle, Washington 98195-7280

Programmed cell death plays an important role both during the development of the CNS and in its homeostasis throughout adulthood. A complex balance between cell death- and survival-inducing signals determines the fate of individual neurons. Intracellular cAMP is thought to regulate neuronal survival, and previous studies have shown that the survival of retinal ganglion cells by brain-derived neurotrophic factor (BDNF) is dependent on cAMP. Here we report the surprising observation that cAMP attenuates the ability of BDNF to rescue cortical neurons from apoptosis after serum deprivation, a process mediated via the phosphatidylinositol 3 (PI3)-kinase signal transduction cascade. Depolarization by KCl, which increases cAMP in cortical neurons, also attenuates BDNF protection against serum withdrawal. Our data indicate that cAMP antagonizes neurotrophin protection from serum withdrawal by inhibiting the PI3-kinase signal transduction cascade. This study indicates that cAMP may inhibit some forms of neurotrophin-mediated neuronal survival and suggests that a number of PI3-kinase-regulated processes in neurons may be inhibited by cAMP.

Key words: PI3-kinase; cAMP; neurotrophins; survival; apoptosis; coincident signaling

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Received Jul. 30, 2002; revised Mar. 4, 2003; accepted Mar. 4, 2003.

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