Inactivation of voltage-gated Ca2+ channels and cone-rod dystrophy CORD7

Minoru Wakamori, Yoshitsugu Uriu, Takafumi Miki, Shigeki Kiyonaka, Yasuo Mori

研究成果: Article査読

抄録

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 influence 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 α1Aα1A/ δβ1a complex in baby hamster kidney cells. During 2-s voltage-displacement 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 affected individuals showed significantly enhanced cognitive abilities across a range of domains. 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 Cavl.4 channels. The data can raise an interesting possibility that CORD7 phenotypes including retinal deficits and enhanced cognition are at least partly due to altered regulation of presynaptic VDCC currents.

本文言語English
ページ(範囲)S53-S62
ジャーナルHirosaki Medical Journal
61
SUPPL.
出版ステータスPublished - 2010 7月 8

ASJC Scopus subject areas

  • 医学(全般)

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