Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Präklinisches Zentrum für Molekulare Signalverarbeitung (PZMS) der Universität des Saarlandes, 66421 Homburg, Germany.
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Präklinisches Zentrum für Molekulare Signalverarbeitung (PZMS) der Universität des Saarlandes, 66421 Homburg, Germany.
Cell Calcium. 2022 Jun;104:102573. doi: 10.1016/j.ceca.2022.102573. Epub 2022 Mar 23.
Independent of its function as a subunit of voltage-gated Ca channels, the Cavβ3 subunit desensitizes fibroblasts and pancreatic β-cells to low concentrations of inositol-1,4,5-trisphosphate (IP3). This alters agonist-induced Ca signaling and cellular functions, for example, insulin secretion and wound healing. A total of four Cavβ subunits exist, Cavβ1, Cavβ2, Cavβ3, and Cavβ4. To investigate whether the other Cavβ subunits, like Cavβ3, can desensitize cells to IP3 and thereby modulate Ca signaling, we expressed the cDNAs of Cavβ1, Cavβ2, Cavβ3, and Cavβ4 in COS-7 cells lacking endogenous Cavβ proteins. ATP stimulation of these cells results in the release of Ca from intracellular stores. This receptor-mediated Ca release is significantly decreased by Cavβ3 but not by Cavβ1, Cavβ2, and Cavβ4. Electrophysiological recordings of voltage-dependent Ca currents from fibroblasts show a small Ca current, the amplitude of which is slightly but not significantly smaller in fibroblasts from Cavβ2 gene-deficient animals than in fibroblasts from wild-type animals. Compared with fibroblasts from wild-type animals, Ca release is not significantly increased in Cavβ2-deficient fibroblasts, in contrast to Ca release in Cavβ3-deficient fibroblasts. In summary, our results show that desensitization of cells to low concentrations of IP3 is a specific property of Cavβ3 that is not shared by other Cavβ subunits.
独立于其作为电压门控 Ca 通道亚基的功能，Cavβ3 亚基使成纤维细胞和胰腺β细胞对低浓度肌醇 1,4,5-三磷酸（IP3）脱敏。这改变了激动剂诱导的 Ca 信号和细胞功能，例如胰岛素分泌和伤口愈合。总共存在四种 Cavβ 亚基，即 Cavβ1、Cavβ2、Cavβ3 和 Cavβ4。为了研究其他 Cavβ 亚基（如 Cavβ3）是否可以使细胞对 IP3 脱敏，从而调节 Ca 信号，我们在缺乏内源性 Cavβ 蛋白的 COS-7 细胞中表达了 Cavβ1、Cavβ2、Cavβ3 和 Cavβ4 的 cDNA。这些细胞中 ATP 的刺激导致细胞内储存的 Ca 释放。这种受体介导的 Ca 释放被 Cavβ3 显著降低，但 Cavβ1、Cavβ2 和 Cavβ4 则不会。对缺乏 Cavβ2 基因的动物来源的成纤维细胞中电压依赖性 Ca 电流的电生理记录显示出较小的 Ca 电流，其幅度在缺乏 Cavβ2 基因的动物来源的成纤维细胞中略小，但无统计学意义，比野生型动物来源的成纤维细胞小。与野生型动物来源的成纤维细胞相比，Cavβ2 缺陷型成纤维细胞中的 Ca 释放没有显著增加，与 Cavβ3 缺陷型成纤维细胞中的 Ca 释放不同。总之，我们的结果表明，细胞对低浓度 IP3 的脱敏是 Cavβ3 的一种特异性特性，其他 Cavβ 亚基则没有这种特性。
