cAMP at Perinuclear mAKAPα Signalosomes Is Regulated by Local Ca²⁺ Signaling in Primary Hippocampal Neurons

Abstract

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 α (mAKAPα/AKAP6α) is sufficient and necessary for axon growth by rat hippocampal neurons in vitro . Here, we report that cAMP at mAKAPα signalosomes is regulated by local Ca 2+ 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 Ca 2+ 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 mAKAPα scaffold, while both perinuclear Ca 2+ elevation and PKA activation were dependent on voltage-dependent L-type Ca 2+ channel activity. Importantly, chelation of Ca 2+ 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 Ca 2+ influx, providing local control for the enhancement of neurite extension.

Astrocytic Calcium and cAMP in Neurodegenerative Diseases

“…These multi-functional scaffold proteins have been widely characterized in neurons, both in physiological and pathological states (Wild and Dell'Acqua, 2018 ). The AKAPs associated with cAMP are regulated by local Ca 2+ oscillations (Scott and Santana, 2010 ; Boczek et al, 2021 ). Global analysis of astroglial transcripts released in 2015 demonstrated that cAMP-dependent signaling regulated 6,221 of 16,594 annotated genes, including 42.1% of them were significantly upregulated whereas the remaining were downregulated by cAMP analogs.…”

Caldendrin represses neurite regeneration and growth in dorsal root ganglion neurons

“…Like the shorter CaBP1 variants, caldendrin could bind to and inhibit inositol 1,4,5 trisphosphate receptors (IP 3 Rs) 46 , 47 and therefore IP 3 R-mediated Ca 2+ signals that are known to enhance DRGN neurite outgrowth 48 . Alternatively, caldendrin might interact with the actin-binding protein cortactin 17 and A-kinase anchoring proteins (AKAPs) 49 , both of which have been implicated in neurite growth regulation 50 , 51 .…”

Caldendrin represses neurite regeneration via a sex-dependent mechanism in sensory neurons

“…Like the shorter CaBP1 variants, caldendrin could bind to and inhibit inositol 1,4,5 trisphosphate receptors (IP 3 Rs) (Haynes et al, 2004; Kasri et al, 2004) and therefore IP 3 R-mediated Ca 2+ signals that are known to enhance DRGN neurite outgrowth (Takei et al, 1998). Alternatively, caldendrin might interact with the actin-binding protein cortactin (Mikhaylova et al, 2018) and A-kinase anchoring proteins (AKAPs) (Gorny et al, 2012), both of which have been implicated in neurite growth regulation (Boczek et al, 2021; Kubo et al, 2015).…”