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首页> 美国卫生研究院文献>The Journal of Pharmacology and Experimental Therapeutics >The Intracellular II-III Loops of Cav1.2 and Cav1.3 Uncouple L-Type Voltage-Gated Ca2+ Channels from Glucagon-Like Peptide-1 Potentiation of Insulin Secretion in INS-1 Cells via Displacement from Lipid Rafts
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The Intracellular II-III Loops of Cav1.2 and Cav1.3 Uncouple L-Type Voltage-Gated Ca2+ Channels from Glucagon-Like Peptide-1 Potentiation of Insulin Secretion in INS-1 Cells via Displacement from Lipid Rafts

机译：Cav1.2和Cav1.3的细胞内II-III环 解除L型电压门控Ca2 +通道与胰高血糖素样的耦合 胰岛素-1肽通过位移增强胰岛素-1细胞中的分泌。 来自Lipid 木筏

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L-type Ca2+ channels play a key role in the integration of physiological signals regulating insulin secretion that probably requires their localization to specific subdomains of the plasma membrane. We investigated the role of the intracellular II-III loop domains of the L-type channels Cav1.2 and 1.3 in coupling of Ca2+ influx with glucose-stimulated insulin secretion (GSIS) potentiated by the incretin hormone glucagon-like peptide (GLP)-1. In INS-1 cell lines expressing the Cav1.2/II-III or Cav1.3/II-III peptides, GLP-1 potentiation of GSIS was inhibited markedly, coincident with a decrease in GLP-1-stimulated cAMP accumulation and the redistribution of Cav1.2 and Cav1.3 out of lipid rafts. Neither the Cav1.2/II-III nor the Cav1.3/II-III peptide decreased L-type current density compared with untransfected INS-1 cells. GLP-1 potentiation of GSIS was restored by the L-type channel agonist 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester (FPL-64176). In contrast, potentiation of GSIS by 8-bromo-cAMP (8-Br-cAMP) was inhibited in Cav1.2/II-III but not Cav1.3/II-III cells. These differences may involve unique protein-protein interactions because the Cav1.2/II-III peptide, but not the Cav1.3/II-III peptide, immunoprecipitates Rab3-interacting molecule (RIM) 2 from INS-1 cell lysates. RIM2, and its binding partner Piccolo, localize to lipid rafts, and they may serve as anchors for Cav1.2 localization to lipid rafts in INS-1 cells. These findings suggest that the II-III interdomain loops of Cav1.2, and possibly Cav1.3, direct these channels to membrane microdomains in which the proteins that mediate potentiation of GSIS by GLP-1 and 8-Br-cAMP assemble.
机译：L型Ca 2 + 通道在调节胰岛素分泌的生理信号的整合中起关键作用，这可能需要将其定位于质膜的特定子域。我们研究了L型通道Cav1.2和1.3的细胞内II-III环域在Ca 2 + 内流与由肠降血糖素增强的葡萄糖刺激的胰岛素分泌（GSIS）耦合中的作用激素胰高血糖素样肽（GLP）-1。在表达Cav1.2 / II-III或Cav1.3 / II-III肽的INS-1细胞系中，GSIS的GLP-1增强被显着抑制，与GLP-1刺激的cAMP积累和重新分布的减少相一致。脂筏中的Cav1.2和Cav1.3的数量。与未转染的INS-1细胞相比，Cav1.2 / II-III或Cav1.3 / II-III肽都不会降低L型电流密度。通过L型通道激动剂2,5-二甲基-4- [2-（苯甲基）苯甲酰基] -1H-吡咯-3-羧酸甲酯（FPL-64176）恢复GSIS的GLP-1增强。相反，Cav1.2 / II-III抑制了8-溴-cAMP（8-Br-cAMP）对GSIS的增强作用，但没有抑制作用 Cav1.3 / II-III细胞。这些差异可能涉及独特 蛋白-蛋白相互作用是因为Cav1.2 / II-III肽，但是 而不是Cav1.3 / II-III肽免疫沉淀Rab3相互作用 INS-1细胞裂解物中的分子（RIM）2。 RIM2及其绑定伙伴 短笛，定位在脂质筏上，它们可能充当锚 Cav1.2定位到INS-1细胞中的脂质筏。这些发现 提示Cav1.2的II-III域间环，以及可能 Cav1.3，将这些通道引导至膜微区，其中 介导GLP-1和8-Br-cAMP增强GSIS的蛋白 组装。

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