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

• Published in: Journal of neurochemistry Vol. 158; no. 2; pp. 182 - 196
• Main Authors: Shumate, Kayla M., Tas, Sadik T., Kavalali, Ege T., Emeson, Ronald B.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2021
• Subjects: ADAR; Adenosine; Adenosine Deaminase - metabolism; Animals; Calcium; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - physiology; CRISPR-Cas Systems; Editing; Electrophysiological Phenomena; GABA; gamma-Aminobutyric Acid - physiology; glutamate; Glutamatergic transmission; Glutamic Acid - physiology; Glycine; High-Throughput Nucleotide Sequencing; Hippocampus; Hippocampus - cytology; Hippocampus - metabolism; Isoforms; Localization; Mice; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neuromodulation; Neuronal Plasticity - genetics; Neuronal Plasticity - physiology; Neurons; Neurotransmission; neurotransmitter; Neurotransmitter release; Neurotransmitters; Primary Cell Culture; Proteins; RNA editing; RNA Editing - genetics; RNA Editing - physiology; Secretion; SNAP receptors; Synapses; Synaptic depression; Synaptic plasticity; Synaptic transmission; Synaptic Transmission - genetics; Synaptic Transmission - physiology; Transcription; γ-Aminobutyric acid; GABA; ADAR; neurotransmitter; glutamate
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.15372

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 adenosine‐to‐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. Sole expression of the Calcium‐dependent activator protein for secretion 1 (CAPS1) isoform encoded by edited Cadps transcripts [CAPS1(G)] results in changes in short‐term plasticity and spontaneous neurotransmission at inhibitory synapses in primary hippocampal cultures without impacting excitatory transmission. CAPS1 is found to be expressed in approximately 85% and 5% of inhibitory and excitatory synapses, respectively, yet editing enhances synaptic localization of the protein to both terminal types. RNA editing of Cadps transcripts and adenosine deaminase acting on RNA (ADAR2) expression are modulated by neuronal activity.