Referenced in: none

Automatically associated channels: Cav1.3

Title: Continuously tunable Ca(2+) regulation of RNA-edited CaV1.3 channels.

Authors: Hojjat Bazzazi, Manu Ben Johny, Paul J Adams, Tuck Wah Soong, David T Yue

Journal, date & volume: Cell Rep, 2013 Oct 31 , 5, 367-77

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24120865

Abstract
CaV1.3 ion channels are dominant Ca(2+) portals into pacemaking neurons, residing at the epicenter of brain rhythmicity and neurodegeneration. Negative Ca(2+) feedback regulation of CaV1.3 channels (CDI) is therefore critical for Ca(2+) 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 Ca(2+)-bound calmodulin (Ca(2+)/CaM) is believed to induce CDI. Here, we sought the mechanism underlying the altered CDI of edited channels. Unexpectedly, editing failed to attenuate Ca(2+)/CaM binding. Instead, editing weakened the prebinding of Ca(2+)-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 Ca(2+) regulation by CaM now looms as a key element of CNS Ca(2+) homeostasis.