FUNCTIONAL ROLE OF RNA EDITING OF CAV1.3 IQ DOMAIN

Abstract

Mutations in human CACNA1D gene encoding the CaV1.3 channel are associated with hearing loss, bradycardia and adrenal aldosterone-producing adenomas; while mCacan1d null mice also showed mood disorder, besides bradycardia and deafness. Alterations in CaV1.3 function will therefore have neurological implications. The IQ-domain of CaV1.3 undergoes A-to-I RNA editing to affect Ca2+-dependent inactivation. Here, we showed that editing is influenced by physiological conditions: (i) RNA editing level increased in substantia nigra during aging and (ii) RNA editing was regulated in a circadian rhythmic fashion in the suprachasmatic nucleus. We discovered the editing site complimentary sequence (ECS) essential for RNA editing by disruption of the hairpin structure using oligonucleotides. We then generated CaV1.3 ECS-/- mice where we demonstrated that RNA editing of the IQ-domain was abolished in these mice. In our initial behavioural studies, we found that the CaV1.3 ECS-/- mice displayed anxiety like behavior and exhibited disruption in their circadian rhythm.