Continuously Tunable Ca²⁺ Regulation of RNA-Edited Ca_V1.3 Channels

Ca_V1.3 ion channels are dominant Ca²⁺ portals into pacemaking neurons, residing at the epicenter of brain rhythmicity and neurodegeneration. Negative Ca²⁺ feedback regulation of Ca_V1.3 channels (CDI) is therefore critical for Ca²⁺ homeostasis. Intriguingly, nearly half the Ca_V1.3 transcripts in the brainare RNA edited to reduce CDI and influence oscillatory activity. It is then mechanistically remarkable that this editing occurs precisely within an IQdomain, 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