Regulation of neuronal survival and axon growth by a perinuclear cAMP compartment

Tomasz Boczek, Evan G. Cameron, Wendou Yu, Xin Xia, Sahil H. Shah, Boris Castillo Chabeco, Joana Galvao, Michael Nahmou, Jinliang Li, Hrishikesh Thakur, Jeffrey L. Goldberg, Michael S. Kapiloff

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

cAMP signaling is known to be critical in neuronal survival and axon growth. Increasingly the subcellular compartmentation of cAMP signaling has been appreciated, but outside of dendritic synaptic regulation, few cAMP compartments have been defined in terms of molecular composition or function in neurons. Specificity in cAMP signaling is conferred in large part by A-kinase anchoring proteins (AKAPs) that localize protein kinase A and other signaling enzymes to discrete intracellular compartments. We now reveal that cAMP signaling within a perinuclear neuronal compartment organized by the large multivalent scaffold protein mAKAPα promotes neuronal survival and axon growth.mAKAPα signalosome function is explored using new molecular tools designed to specifically alter localcAMP levels as studied by live-cell FRET imaging. In addition, enhancement of mAKAPα-associated cAMP signaling by isoform-specific displacement of bound phosphodiesterase is demonstrated to increase retinal ganglion cell survival in vivo in mice of both sexes following optic nerve crush injury. These findings define a novel neuronal compartment that conferscAMPregulation of neuroprotection and axon growth and that may be therapeutically targeted in disease.

Original languageEnglish (US)
Pages (from-to)5466-5480
Number of pages15
JournalJournal of Neuroscience
Volume39
Issue number28
DOIs
StatePublished - Jul 10 2019

Keywords

  • cAMP
  • FRET imaging
  • Neuroprotection
  • Phosphodiesterase
  • Signal transduction
  • Signalosome

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Boczek, T., Cameron, E. G., Yu, W., Xia, X., Shah, S. H., Chabeco, B. C., Galvao, J., Nahmou, M., Li, J., Thakur, H., Goldberg, J. L., & Kapiloff, M. S. (2019). Regulation of neuronal survival and axon growth by a perinuclear cAMP compartment. Journal of Neuroscience, 39(28), 5466-5480. https://doi.org/10.1523/JNEUROSCI.2752-18.2019