Cellular and Molecular Neurobiology ( IF 4 ) Pub Date : 2020-11-20 , DOI: 10.1007/s10571-020-01002-1 Mizuho Horioka 1, 2 , Emilie Ceraudo 2 , Emily Lorenzen 2 , Thomas P Sakmar 2 , Thomas Huber 2
Many G protein-coupled receptors (GPCRs) signal through more than one subtype of heterotrimeric G proteins. For example, the C–C chemokine receptor type 5 (CCR5), which serves as a co-receptor to facilitate cellular entry of human immunodeficiency virus 1 (HIV-1), normally signals through the heterotrimeric G protein, Gi. However, CCR5 also exhibits G protein signaling bias and certain chemokine analogs can cause a switch to Gq pathways to induce Ca2+ signaling. We want to understand how much of the Ca2+ signaling from Gi-coupled receptors is due to G protein promiscuity and how much is due to transactivation and crosstalk with other receptors. We propose a possible mechanism underlying the apparent switching between different G protein signaling pathways. We show that chemokine-mediated Ca2+ flux in HEK293T cells expressing CCR5 can be primed and enhanced by ATP pretreatment. In addition, agonist-dependent lysosomal exocytosis results in the release of ATP to the extracellular milieu, which amplifies cellular signaling networks. ATP is quickly degraded via ADP and AMP to adenosine. ATP, ADP and adenosine activate different cell surface purinergic receptors. Endogenous Gq-coupled purinergic P2Y receptors amplify Ca2+ signaling and allow for Gi- and Gq-coupled receptor signaling pathways to converge. Associated secretory release of GPCR ligands, such as chemokines, opioids, and monoamines, should also lead to concomitant release of ATP with a synergistic effect on Ca2+ signaling. Our results suggest that crosstalk between ATP-activated purinergic receptors and other Gi-coupled GPCRs is an important cooperative mechanism to amplify the intracellular Ca2+ signaling response.
中文翻译:
嘌呤能受体与 CCR5 串扰以放大 Ca 2+ 信号
许多 G 蛋白偶联受体 (GPCR) 通过一种以上的异源三聚体 G 蛋白亚型发出信号。例如,C-C 趋化因子受体 5 (CCR5) 作为辅助受体促进人类免疫缺陷病毒 1 (HIV-1) 进入细胞,通常通过异源三聚体 G 蛋白 Gi 发出信号。然而,CCR5 也表现出 G 蛋白信号偏向性,某些趋化因子类似物可导致转换为 Gq 通路以诱导 Ca 2+信号。我们想了解多少 Ca 2+来自 Gi 偶联受体的信号传导是由于 G 蛋白混杂,而有多少是由于与其他受体的反式激活和串扰。我们提出了不同 G 蛋白信号通路之间明显切换的潜在机制。我们表明,表达 CCR5 的 HEK293T 细胞中趋化因子介导的 Ca 2+通量可以通过 ATP 预处理引发和增强。此外,激动剂依赖性溶酶体胞吐作用导致 ATP 释放到细胞外环境,从而放大细胞信号网络。ATP 通过 ADP 和 AMP 迅速降解为腺苷。ATP、ADP 和腺苷激活不同的细胞表面嘌呤能受体。内源性 Gq 偶联的嘌呤能 P2Y 受体放大 Ca 2+信号并允许 Gi 和 Gq 偶联的受体信号通路收敛。GPCR 配体(例如趋化因子、阿片类药物和单胺)的相关分泌释放也应导致 ATP 的伴随释放,并对 Ca 2+信号传导产生协同作用。我们的结果表明,ATP 激活的嘌呤能受体和其他 Gi 偶联 GPCR 之间的串扰是放大细胞内 Ca 2+信号反应的重要合作机制。