＜Syposium II＞Inactivation of voltage-gated Ca^2+ channels and cone-rod dystrophy CORD7

Active zones are highly specialized sites for release of neurotransmitter in presynaptic nerve terminals. The spacing between voltage-dependent calcium channels（ VDCCs） and synaptic vesicles at active zones is thought to infl uence the dynamic properties of synaptic transmission. Recently we have demonstrated a novel molecular interaction between VDCCs and an active zone scaffolding protein, rab3-interacting molecule 1 （RIM1）. The RIM1 induced a pronounced deceleration of inactivation rate and a depolarizing shift of the inactivation curve of recombinant P/Q-type VDCC expressed as α1Aα2/δβ1a complex in baby hamster kidney cells. During 2-s voltagedisplacement to -30 mV, which is the threshold of the P/Q-type VDCC activation, almost all channels were inactivated in the absence of the RIM1 （closed-state inactivation）, but less than 20% of the channels were inactivated in the presence of the RIM1. Thus, the RIM1 coordinates calcium signaling and spatial organization of molecular constituents at presynaptic active zone. A mutation has been identified for an autosomal dominant cone-rod dystrophy CORD7 in the RIM1 gene. Interestingly, the aff ected individuals showed signifi cantly enhanced cognitive abilities across a range of domains. The mouse RIM1 arginine-to-histidine substitution （R655H）, which corresponds to the human CORD7 mutation, modifi es RIM1 function in regulating VDCC currents elicited by the P/Q-type Cav2.1 and L-type Cav1.4 channels. The data can raise an interesting possibility that CORD7 phenotypes including retinal defi cits and enhanced cognition are at least partly due to altered regulation of presynaptic VDCC currents