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

Ca(V)1.3 ion channels are dominant Ca2+ portals into pacemaking neurons, residing at the epicenter of brain rhythmicity and neurodegeneration. Negative Ca2+ feedback regulation of Ca(V)1.3 channels (CDI) is therefore critical for Ca2+ homeostasis. Intriguingly, nearly half the Ca(V)1.3 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.