PDF(Pubmed)
Abstract：
Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are high-conductance channels that allow the regulated redistribution of Ca2+ from the endoplasmic reticulum (ER) to the cytosol and, at specialized membrane contact sites (MCSs), to other organelles. Only a subset of IP3Rs release Ca2+ to the cytosol in response to IP3. These \'licensed\' IP3Rs are associated with Kras-induced actin-interacting protein (KRAP, also known as ITPRID2) beneath the plasma membrane. It is unclear whether KRAP regulates IP3Rs at MCSs. We show, using simultaneous measurements of Ca2+ concentration in the cytosol and mitochondrial matrix, that KRAP also licenses IP3Rs to release Ca2+ to mitochondria. Loss of KRAP abolishes cytosolic and mitochondrial Ca2+ signals evoked by stimulation of IP3Rs via endogenous receptors. KRAP is located at ER-mitochondrial membrane contact sites (ERMCSs) populated by IP3R clusters. Using a proximity ligation assay between IP3R and voltage-dependent anion channel 1 (VDAC1), we show that loss of KRAP reduces the number of ERMCSs. We conclude that KRAP regulates Ca2+ transfer from IP3Rs to mitochondria by both licensing IP3R activity and stabilizing ERMCSs.
摘要：
肌醇1,4,5-三磷酸受体（IP3Rs）是高电导通道，允许调节Ca2+从ER到细胞质的再分布，在专门的膜接触位点(MCS)，其他细胞器。只有一部分IP3R响应于IP3将Ca2+释放到胞质溶胶。这些许可的IP3R与质膜下的Kras诱导的肌动蛋白相互作用蛋白（KRAP）相关。目前尚不清楚KRAP是否在MCS时调节IP3Rs。我们展示,同时测量细胞质和线粒体基质中的Ca2+浓度，KRAP还授权IP3Rs向线粒体释放Ca2+。KRAP的缺失消除了通过内源性受体刺激IP3R引起的胞浆和线粒体Ca2信号。KRAP位于由IP3R簇填充的ER-线粒体膜接触位点(ERMCS)。使用IP3R和电压依赖性阴离子通道1（VDAC1）之间的邻近连接测定，我们表明KRAP的丢失减少了ERMCS的数量。我们得出的结论是，KRAP通过许可IP3R活性和稳定ERMCS来调节从IP3R到线粒体的Ca2转移。
