Mutation associated with an autosomal dominant cone-rod dystrophy CORD7 modifies RIM1-mediated modulation of voltage-dependent Ca2+ channels

摘要

Genetic analyses have revealed an association of the gene encoding the Rab3A-interacting molecule (RIM1) with an autosomal dominant cone-rod dystrophy CORD7. However, the pathogenesis of CORD7 has remained unclear. Recently, we have revealed that RIM1 exerts functional impacts on voltage-dependent Ca²⁺ channel (VDCC) currents and anchors neurotransmitter-containing vesicles to VDCCs, controlling neurotransmitter release. On the basis of this study, we demonstrate here that the mouse RIM1 arginine-to-histidine substitution (R655H), which corresponds to the human CORD7 mutation, modifies RIM1 function in regulating VDCC currents elicited by the P/Q-type Cav2.1 and L-type Cav1.4 channels. Thus, we can raise an interesting possibility that CORD7 phenotypes including retinal deficits and enhanced cognition are at least partly underlaid by altered regulation of presynaptic VDCC currents.