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Title: Functional Diversity of Cav1.3 Channels Generated by RNA Editing and Alternative Splicing
Authors: HUANG HUA
Keywords: RNA editing, Alternative splicing, CaV1.3 Channels, neuronal pacemaking, IQ domain, channel properties, drug sensitivity
Issue Date: 26-Jul-2011
Citation: HUANG HUA (2011-07-26). Functional Diversity of Cav1.3 Channels Generated by RNA Editing and Alternative Splicing. ScholarBank@NUS Repository.
Abstract: Post-transcriptional modifications including A-to-I RNA editing and alternative splicing are important mechanisms for generating molecular diversity of mammalian ion channels and receptors. Here, we discover RNA editing within CaV1.3 transcripts that encode Ca2+ channels that are known for low voltage activated Ca2+-influx and neuronal pacemaking. Significantly, RNA editing occurs within the IQ domain, a calmodulin-binding site mediating inhibitory Ca2+-feedback (CDI) on the channels. RNA editing of the CaV1.3 IQ domain is CNS-specific, requires RNA adenosine deaminase 2 (ADAR2), and is evolutionally conserved from human, rat to mouse. Functionally, edited CaV1.3 channels exhibit strong attenuation of CDI, and neurons in the suprachiasmatic nucleus show higher frequencies of repetitive action potential activity and calcium spikes in wildtype versus ADAR2-/- knockout mice. Apart from RNA editing, the transcripts of CaV1.3 channels are extensively alternatively spliced at exons coding for IS5-IS6, I-II loop and IVS3-IVS4. Alternative splicing in the IS5-IS6, I-II loop significantly affect the activation potential of the channel while IVS3-IVS4 splicing alters the channel sensitivity towards dihydropyridine inhibition. Tissue selective expression of different splice isoforms therefore customizes channel functions for different physiological needs.
Appears in Collections:Ph.D Theses (Open)

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