期刊
ENEURO
卷 8, 期 1, 页码 -出版社
SOC NEUROSCIENCE
DOI: 10.1523/ENEURO.0298-20.2021
关键词
AKAP; cAMP; compartment; FRET imaging; PKA; signaling
资金
- National Institutes of Health [R01 EY026766, P30 EY026877, R01 HL126825, R01 HL146111, R01 EY031167]
- Stanford Center for Optic Disc Drusen
- Research to Prevent Blindness, Inc.
This study demonstrates that a neuronal perinuclear cAMP compartment is locally regulated by activity-dependent Ca2+ influx, providing local control for the enhancement of neurite extension.
The second messenger cyclic adenosine monophosphate (cAMP) is important for the regulation of neuronal structure and function, including neurite extension. A perinuclear cAMP compartment organized by the scaffold protein muscle A-kinase anchoring protein a (mAKAPa/AKAP6a) is sufficient and necessary for axon growth by rat hippocampal neurons in vitro. Here, we report that cAMP at mAKAPa signalosomes is regulated by local Ca2+ signaling that mediates activity-dependent cAMP elevation within that compartment. Simultaneous Forster resonance energy transfer (FRET) imaging using the protein kinase A (PKA) activity reporter AKAR4 and intensiometric imaging using the RCaMP1h fluorescent Ca2+ sensor revealed that membrane depolarization by KCl selectively induced activation of perinuclear PKA activity. Activity-dependent perinuclear PKA activity was dependent on expression of the mAKAPa scaffold, while both perinuclear Ca2+ elevation and PKA activation were dependent on voltage -dependent L-type Ca2+ channel activity. Importantly, chelation of Ca2+ by a nuclear envelope-localized parvalbumin fusion protein inhibited both activity-induced perinuclear PKA activity and axon elongation. Together, this study provides evidence for a model in which a neuronal perinuclear cAMP compartment is locally regulated by activity-dependent Ca2+ influx, providing local control for the enhancement of neurite extension.
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