Functional outcomes of Cadps A-to-I RNA editing in the nervous and endocrine systems

Abstract

Regulated exocytosis is the process that directs the release of neurotransmitters and peptide hormones from neurons and endocrine cells. CAPS1, calcium-dependent activator protein for secretion 1, is a SNARE accessory protein that augments regulated exocytosis in the endocrine and central nervous systems. An adenosine-to-inosine RNA editing event occurs within Cadps transcripts to alter its coding potential from a genomically-encoded glutamate to glycine codon in a region encoding the carboxyl-terminal domain of the protein. Investigation of the cellular and physiological roles of Cadps editing was undertaken using mutant mice that solely express either non-edited or edited isoform of CAPS1. Cadps editing enhanced dopaminergic neurotransmission specifically in the dorsal striatum measured in ex vivo brain slices, and behavioral outcomes associated with enhanced dopamine signaling in this brain region, including hyperactivity and repetitive rearing, were identified in edited CAPS1 animals. Cadps editing also enhanced short-term depression and mIPSC amplitudes in GABAergic synapses of primary hippocampal neurons, while glutamatergic transmission remained unaltered, an effect likely driven by the low extent of CAPS1 localization to excitatory synapses. Editing of Cadps RNAs enhanced synaptic localization of CAPS1 to both glutamatergic and GABAergic terminals, suggesting a potential mechanism by which Cadps editing enhances neurotransmission. In addition, the levels of Cadps editing were found to be modulated by neuronal activity. No substantial Cadps-editing dependent changes in hormone release were identified. These studies provide key insights into the regulation of CAPS1 editing and further our knowledge of the cellular and physiological outcomes associated with altered CAPS1 editing.