RNA editing‐mediated regulation of calcium‐dependent activator protein for secretion (CAPS1) localization and its impact on synaptic transmission

Abstract

Calcium-dependent activator protein for secretion 1 (CAPS1) is a SNARE accessory protein that facilitates formation of the SNARE complex to enable neurotransmitter release. Messenger RNAs encoding CAPS1 are subject to a site-specific adenosineto-inosine (A-to-I) editing event resulting in a glutamate-to-glycine (E-to-G) substitution in the C-terminal domain of the encoded protein product. The C-terminal domain of CAPS1 is necessary for its synaptic enrichment and Cadps RNA editing has been shown previously to enhance the release of neuromodulatory transmitters. Using mutant mouse lines engineered to solely express CAPS1 protein isoforms encoded by either the non-edited or edited Cadps transcript, primary neuronal cultures from mouse hippocampus were used to explore the effect of Cadps editing on neurotransmission and CAPS1 synaptic localization at both glutamatergic and GABAergic synapses. While the editing of Cadps does not alter baseline evoked neurotransmission, it enhances short-term synaptic plasticity, specifically short-term depression, at inhibitory synapses. Cadps editing also alters spontaneous inhibitory neurotransmission. Neurons that solely express edited Cadps have a greater proportion of synapses that contain CAPS1 than neurons that solely express non-edited Cadps for both glutamatergic and GABAergic synapses. Editing of Cadps transcripts is regulated by neuronal activity, as global network stimulation increases the extent of transcripts edited in wild-type hippocampal neurons, whereas chronic network silencing decreases the level of Cadps editing. Taken together, these results provide key insights into the importance of Cadps editing in modulating its own synaptic localization, as well as the modulation of neurotransmission at inhibitory synapses in hippocampal neurons.

Spatiotemporal and genetic regulation of A-to-I editing throughout human brain development

“… 51 Third, a ~20% increase in the p.E1171G site in calcium-dependent secretion activator ( CADPS ) was observed, a site with high editing levels reported in glumatergic neurons. 31 Increased editing at this site has been shown to increase expression and synaptic localization of CADPS and enhance short-term synaptic plasticity, 52 which may have significant neuronal network effects throughout brain development. Fourth, divergent temporal editing profiles were observed for p.K95R in insulin-like growth factor-binding protein 7 ( IGFBP7 ), a site that decreases ~25% in the cortex but increases ~25% in the cerebellum across development.…”

Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in inbred and recombinant inbred mice

“…Significant GO enrichments were found for brain region and sex, including cellular and primary metabolic process for brain region, and chromosome organization and histone modification for sex (Supplementary Figures S15, S18 and S20). Of the 299 editing sites significantly regulated by brain region, 13 resulted in non-synonymous coding region changes, including Cadps, Tmem63b, Unc80 and Cyfip2 (Supplementary Figure S19) (Cuddleston et al, 2022; Shumate et al, 2021; Tariq et al, 2013; Wu et al, 2020).…”

“…Of the 299 editing sites significantly regulated by brain region, 13 resulted in non-synonymous coding region changes, including Cadps , Tmem63b , Unc80 and Cyfip2 (Supplementary Figure S19) (Cuddleston et al, 2022; Shumate et al, 2021; Tariq et al, 2013; Wu et al, 2020).…”

Localization of the Priming Factors CAPS1 and CAPS2 in Mouse Sensory Neurons Is Determined by Their N-Termini

“…Synaptic localization of CAPS1 in hippocampal neurons are associated with the C-terminal region containing the DCV and MHD domains ( van Keimpema et al, 2017 ). Recently a C-terminal amino acid at position 1252 that is subject to RNA editing from glutamate-to-glycine has been shown to be involved in CAPS1 synaptic localization ( Shumate et al, 2021 ). However, the C-terminal region is highly conserved and has a similar domain structure in both CAPS paralogs ( Speidel et al, 2003 ).…”