, 1997 and Seeburg et al., 1998). Functionally, the adenosine deaminase enzyme ADAR2 is responsible for RNA editing that recodes a glutamine to arginine in the selectivity filter of GluR-B subunits (“Q/R editing” of GluR-B); consequently, ADAR2 knockout mice exhibit increased Ca2+ permeability, with concomitant epilepsy and death (Higuchi et al., 2000). More broadly, a generalized dysregulation of brain RNA editing in humans may contribute to epilepsy, depression, and suicidal tendencies (Gurevich et al., 2002, Schmauss, 2003 and Sergeeva et al., 2007). Indeed, it is BMN 673 purchase likely that numerous other editing

substrates remain to be identified in the mammalian brain, given the high inosine content DAPT molecular weight of mRNA in neural tissue (Paul and Bass, 1998). In particular, we wondered whether RNA editing might fine-tune the calmodulin (CaM) regulation of voltage-gated calcium channels (VGCCs). This Ca2+ feedback regulation would be an especially attractive target for editing, because structure-function analysis

reveals that even single amino acid substitutions at critical channel hotspots can markedly alter modulatory properties (Dick et al., 2008, Tadross et al., 2008 and Zühlke et al., 2000), and such regulation impacts functions as diverse as neurotransmitter release, neuronal pacemaking, neurite outgrowth, and gene expression (Dunlap, 2007). Figure 1A cartoons such regulatory hotspots, which are located

on the amino- and carboxyl-termini of the pore-forming α1 subunits of VGCCs. The best-studied locus is a CaM-binding domain approximating a consensus IQ element satisfying Thymidine kinase the amino acid pattern IQxxxRGxxxR (Jurado et al., 1999), with x denoting any residue. CaM binding at this IQ domain is critical for CaM/channel regulation (Liu et al., 2010), and mutations in the central isoleucine strongly attenuate Ca2+ regulation (Shen et al., 2006 and Yang et al., 2006). Here, we reveal the existence of ADAR2-mediated RNA editing of the IQ domain of CaV1.3 channels. This editing appears specific to the central nervous system, and proteomic analyses indeed confirm the presence of edited CaV1.3 channel proteins within native brain tissues. Adding to the theme of specificity, no RNA editing was found for CaV1.3 coding regions outside of the IQ domain, nor was IQ-domain editing present in any other members of the CaV1-2 channel family. All these features suggest that CaV1.3 editing may entail distinctive sequelae for the CaM-dependent inactivation (CDI) of these channels, particularly in relation to the availability of these low-voltage activated channels to support neurotransmission at ribbon synapses (Evans and Zamponi, 2006 and Yang et al., 2006) and repetitive firing within neurons throughout the brain (Chan et al., 2007). Accordingly, we demonstrate that RNA editing of the CaV1.