RNA Editing of the IQ Domain in CaV1.3 Channels Modulates their Ca2+-Dependent Inactivation

Adenosine-to-inosine RNA editing generates molecular diversity and serves to regulate protein function via recoding of genomic information. Here, we report discovery of editing within CaV1.3 Ca2+ channels, well-known for low-voltage Ca2+-influx and neuronal pacemaking. Significantly, editing results in amino acid changes within the channel's IQ domain, a calmodulin-binding site mediating inhibitory Ca2+-feedback (CDI) on channels. The editing turns out to require RNA adenosine deaminase ADAR2 which recognizes a RNA duplex structure formed by the edited sites and intronic complementary sequence. The variable activity of ADAR2 potentially underlies a spatially diverse pattern of CaV1.3 editing seen across the brain. Edited CaV1.3 protein is detected both in brain tissue and within the surface membrane of primary neurons. Functionally, edited CaV1.3 channels exhibit strong reduction of CDI; in particular, neurons within the suprachiasmatic nucleus show diminished CDI, with higher frequencies of repetitive action-potential and calcium-spike activity, in wildtype versus ADAR2 knockout mice. Our study reveals a mechanism for fine-tuning CaV1.3 channel properties in CNS, which likely impacts a broad spectrum of neurobiological functions.