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The Journal of Neuroscience, February 1, 2003, 23(3):777
An Extranuclear Locus of cAMP-Dependent Protein Kinase Action Is Necessary and Sufficient for Promotion of Spiral Ganglion Neuronal Survival by cAMP
Jinwoong Bok1, Xiang-Ming Zha1, Yang-Sun Cho1, 2, and Steven H. Green1 1 Departments of Biological Sciences and Otolaryngology, University of Iowa, Iowa City, Iowa 52242, and 2 Department of Otorhinolaryngology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 135-710
We showed previously that cAMP is a survival-promoting stimulus for cultured postnatal rat spiral ganglion neurons (SGNs) and that depolarization promotes SGN survival in part via recruitment of cAMP signaling. We here investigate the subcellular locus of cAMP prosurvival signaling. Transfection of GPKI, a green fluorescent protein (GFP)-tagged cAMP-dependent protein kinase (PKA) inhibitor, inhibits the ability of the permeant cAMP analog cpt-cAMP [8-(4-chlorophenylthio)-cAMP] to promote survival, indicating that PKA activity is necessary. Transfection of GFP-tagged PKA (GPKA) is sufficient to promote SGN survival, but restriction of GPKA to the nucleus by addition of a nuclear localization signal (GPKAnls) almost completely abrogates its prosurvival effect. In contrast, GPKA targeted to the extranuclear cytoplasm by addition of a nuclear export signal (GPKAnes) promotes SGN survival as effectively as does GPKA. Moreover, GPKI targeted to the nucleus lacks inhibitory effect on SGN survival attributable to cpt-cAMP or depolarization. These data indicate an extranuclear target of PKA for promotion of neuronal survival. Consistent with this, we find that dominant-inhibitory CREB mutants inhibit the prosurvival effect of depolarization but not that of cpt-cAMP. SGN survival is compromised by overexpression of the proapoptotic regulator Bad, previously shown to be phosphorylated in the cytoplasm by PKA. This Bad-induced apoptosis is prevented by cpt-cAMP or by cotransfection of GPKA or of GPKAnes but not of GPKAnls. Thus, cAMP prevents SGN death through a cytoplasmic as opposed to nuclear action, and inactivation of Bad proapoptotic function is a mechanism by which PKA can prevent neuronal death.
Key words: membrane depolarization; spiral ganglion neuron; cell survival; cAMP; cAMP-dependent protein kinase; PKA; apoptosis; Bad; intracellular signal; CREB
Copyright © 2003 Society for Neuroscience 0270-6474/03/233777-11$05.00/0
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