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Abstract

Adenosine−to−inosine RNA editing is crucial for generating molecular diversity, and serves to regulate protein function through recoding of genomic information. Here, we discover editing within CaV1.3 Ca2+ channels, renown for low−voltage Ca2+−influx and neuronal pacemaking. Significantly, editing occurs 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, whose variable activity could underlie 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 wild−type 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