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

International audienceGenetic analyses have revealed an association between the gene encoding the Rab3A-interacting molecule (RIM1) and the autosomal dominant cone-rod dystrophy CORD7. However, the pathogenesis of CORD7 remains unclear. We recently revealed that RIM1 regulates voltage-dependent Ca(2+) channel (VDCC) currents and anchors neurotransmitter-containing vesicles to VDCCs, thereby controlling neurotransmitter release. 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 Ca(v)2.1 and L-type Ca(v)1.4 channels. Thus, our 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

RIM1 confers sustained activity and neurotransmitter vesicle anchoring to presynaptic Ca2+ channels.

International audienceThe molecular organization of presynaptic active zones is important for the neurotransmitter release that is triggered by depolarization-induced Ca2+ influx. Here, we demonstrate a previously unknown interaction between two components of the presynaptic active zone, RIM1 and voltage-dependent Ca2+ channels (VDCCs), that controls neurotransmitter release in mammalian neurons. RIM1 associated with VDCC beta-subunits via its C terminus to markedly suppress voltage-dependent inactivation among different neuronal VDCCs. Consistently, in pheochromocytoma neuroendocrine PC12 cells, acetylcholine release was significantly potentiated by the full-length and C-terminal RIM1 constructs, but membrane docking of vesicles was enhanced only by the full-length RIM1. The beta construct beta-AID dominant negative, which disrupts the RIM1-beta association, accelerated the inactivation of native VDCC currents, suppressed vesicle docking and acetylcholine release in PC12 cells, and inhibited glutamate release in cultured cerebellar neurons. Thus, RIM1 association with beta in the presynaptic active zone supports release via two distinct mechanisms: sustaining Ca2+ influx through inhibition of channel inactivation, and anchoring neurotransmitter-containing vesicles in the vicinity of VDCCs

神経伝達に関わるCa2+チャネル複合体の生化学・生物物理学的解明

京都大学0048新制・課程博士博士(工学)甲第15675号工博第3333号新制||工||1503(附属図書館)28212京都大学大学院工学研究科合成・生物化学専攻(主査)教授 森 泰生, 教授 跡見 晴幸, 教授 濵地 格学位規則第4条第1項該当Doctor of Philosophy (Engineering)Kyoto UniversityDFA

CyclinG1-PP2A B´γ フクゴウタイ ノ ケツゴウ ヲ ソガイ スル ELAS1 ペプチド ハ p53 ノ アンテイカ ト カッセイカ ヲ カイシテ ガン サイボウ ヲ アポトースス ヘ ユウドウ スル

SummaryInsulin secretion is essential for maintenance of glucose homeostasis, but the mechanism of insulin granule exocytosis, the final step of insulin secretion, is largely unknown. Here, we investigated the role of Rim2α in insulin granule exocytosis, including the docking, priming, and fusion steps. We found that interaction of Rim2α and Rab3A is required for docking, which is considered a brake on fusion events, and that docking is necessary for K+-induced exocytosis, but not for glucose-induced exocytosis. Furthermore, we found that dissociation of the Rim2α/Munc13-1 complex by glucose stimulation activates Syntaxin1 by Munc13-1, indicating that Rim2α primes insulin granules for fusion. Thus, Rim2α determines docking and priming states in insulin granule exocytosis depending on its interacting partner, Rab3A or Munc13-1, respectively. Because Rim2α−/− mice exhibit impaired secretion of various hormones stored as dense-core granules, including glucose-dependent insulinotropic polypeptide, growth hormone, and epinephrine, Rim2α plays a critical role in exocytosis of these dense-core granules