Department of Pharmacology, Tennis Court Road, Cambridge, UK.
Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar.
Nat Commun. 2021 Jul 23;12(1):4514. doi: 10.1038/s41467-021-24739-9.
Regulation of IP receptors (IPRs) by IP and Ca allows regenerative Ca signals, the smallest being Ca puffs, which arise from coordinated openings of a few clustered IPRs. Cells express thousands of mostly mobile IPRs, yet Ca puffs occur at a few immobile IPR clusters. By imaging cells with endogenous IPRs tagged with EGFP, we show that KRas-induced actin-interacting protein (KRAP) tethers IPRs to actin beneath the plasma membrane. Loss of KRAP abolishes Ca puffs and the global increases in cytosolic Ca concentration evoked by more intense stimulation. Over-expressing KRAP immobilizes additional IPR clusters and results in more Ca puffs and larger global Ca signals. Endogenous KRAP determines which IPRs will respond: it tethers IPR clusters to actin alongside sites where store-operated Ca entry occurs, licenses IPRs to evoke Ca puffs and global cytosolic Ca signals, implicates the actin cytoskeleton in IPR regulation and may allow local activation of Ca entry.
IP 和 Ca 对 IP 受体 (IPRs) 的调节允许再生 Ca 信号，最小的是 Ca 脉冲，它来自几个簇集的 IPR 的协调开放。细胞表达成千上万种主要是可移动的 IPR，但 Ca 脉冲发生在少数不可移动的 IPR 簇中。通过用 EGFP 标记内源性 IPR 对细胞进行成像，我们表明，Ras 诱导的肌动蛋白相互作用蛋白 (KRAP) 将 IPR 固定在质膜下的肌动蛋白上。KRAP 的缺失会消除 Ca 脉冲和更强烈刺激引起的细胞溶质 Ca 浓度的全局增加。过表达 KRAP 会固定额外的 IPR 簇，并导致更多的 Ca 脉冲和更大的全局 Ca 信号。内源性 KRAP 决定哪些 IPR 将做出响应：它将 IPR 簇固定在肌动蛋白旁边，存储操作 Ca 进入发生的部位，许可 IPR 引发 Ca 脉冲和全局细胞溶质 Ca 信号，暗示肌动蛋白细胞骨架参与 IPR 调节，并可能允许局部激活 Ca 进入。
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