Continuously Tunable Ca2+ Regulation of RNA-Edited CaV1.3 Channels

•Unexpected mechanism explains how RNA editing tunes Ca2+ channel regulation by CaM•Substantiates major role of Ca2+ channel IQ domain to tether Ca2+-free calmodulin•Fluctuations in ambient calmodulin predicted to tune Ca2+ homeostasis across the brain•Elevated calmodulin enhances Ca2+ regulation of Ca2+ channels in substantia nigra

SummaryCaV1.3 ion channels are dominant Ca2+ portals into pacemaking neurons, residing at the epicenter of brain rhythmicity and neurodegeneration. Negative Ca2+ feedback regulation of CaV1.3 channels (CDI) is therefore critical for Ca2+ homeostasis. Intriguingly, nearly half the CaV1.3 transcripts in the brain are RNA edited to reduce CDI and influence oscillatory activity. It is then mechanistically remarkable that this editing occurs precisely within an IQ domain, whose interaction with Ca2+-bound calmodulin (Ca2+/CaM) is believed to induce CDI. Here, we sought the mechanism underlying the altered CDI of edited channels. Unexpectedly, editing failed to attenuate Ca2+/CaM binding. Instead, editing weakened the prebinding of Ca2+-free CaM (apoCaM) to channels, which proves essential for CDI. Thus, editing might render CDI continuously tunable by fluctuations in ambient CaM, a prominent effect we substantiate in substantia nigral neurons. This adjustability of Ca2+ regulation by CaM now looms as a key element of CNS Ca2+ homeostasis.

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