What is it about?

RNA editing occurs post-transcriptionally, that is after the production of the pre-mRNA, to recode the genomic information such that altered codon codes for a different amino acid. Unlike a genetic mutation, the recoding of the genome is not hard-wired by the RNA editing process. More than 15 years ago, we discovered that the CaV1.3 channel transcript could be RNA edited at 3 sites with a regulatory motif called the IQ-domain. We first published this discovery in 2012 (Huang et al, Neuron 2012), and subsequently also provided evidence for the regulation of CaV1.3 RNA editing be the splicing factor SRSF9 (Huang et al NAR 2018).

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Why is it important?

Here, in the PNAS publication (Zhai et al PNAS 2022), we examined the physiological importance of the loss of CaV1.3 RNA editing by genetically deleting a genomic region called the “Editing-site Complementary Sequence” or ECS from the mouse genome in order to abolish the ability of the transgenic mouse (named Cav1.3ECS) to RNA edit the CaV1.3 transcript. We subjected the CaV1.3ECS mice to behavioural tests and discovered that they displayed enhanced ability in spatial learning and memory as compared to their wild-type littermates. As CaV1.3 is not known to be involved in hippocampal learning and memory, we sought to uncover the underlying mechanisms for this observed phenomenon. We discovered firstly that the loss of RNA editing resulted in a CaV1.3 gain-of-function and more Ca2+ ions could flow through the unedited CaV1.3 channels into the neurons. This finding also resolved a paradox as editing affects CaV1.3 function in diametrically opposite ways – to slow the closure of the channel to allow more Ca2+ ions influx or to decrease the channel’s probability of opening to decrease Ca2+ ions influx. As the loss of editing produced a gain-of-function in the unedited CaV1.3 channels in CaV1.3ECS neurons, we next investigated and found that the hippocampal neurons were more excitable due to a more depolarized resting potential and firing of action potential was more easily evoked. This led to both increased presynaptic neurotransmitter release as well as enhanced postsynaptic receptor response.

Perspectives

Of note, CaV1.3 RNA editing is not only evolutionarily conserved across species, but is also tuneable in response to training in learning and memory. However, a critical question to ask is whether there are trade-offs as the codon changes in the 3 editing sites of CaV1.3 were not hardwired in the genome? Indeed, our current research has uncovered trade-offs that we aim to publish in the near future.

Tuck Wah Soong
National University of Singapore Medical Library

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This page is a summary of: Loss of Ca V 1.3 RNA editing enhances mouse hippocampal plasticity, learning, and memory, Proceedings of the National Academy of Sciences, August 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2203883119.
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