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 Ca V1.3 Ca 2+ channels, renown for low-voltage Ca 2+-influx and neuronal pacemaking. Significantly, editing occurs within the channel's IQ domain, a calmodulin-binding site mediating inhibitory Ca 2+-feedback (CDI) on channels. The editing turns out to require RNA adenosine deaminase ADAR2, whose variable activity could underlie a spatially diverse pattern of Ca V1.3 editing seen across the brain. Edited Ca V1.3 protein is detected both in brain tissue and within the surface membrane of primary neurons. Functionally, edited Ca V1.3 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 Ca V1.3 channel properties in CNS, which likely impacts a broad spectrum of neurobiological functions. Huang et al. find that RNA editing of the voltage-gated calcium channel Cav1.3 IQ domain acts as a regulatory mechanism for calcium-dependent channel inactivation. Given widespread roles for Cav1.3 channels invivo, this mechanism may have consequences for a broad range of physiological functions.
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