Departments of Surgery and Physiology, University of California, San Francisco, CA 94143, USA.
Biochem Soc Trans. 2013 Feb 1;41(1):137-43. doi: 10.1042/BST20120343.
GPCR (G-protein-coupled receptor) signalling at the plasma membrane is under tight control. In the case of neuropeptides such as SP (substance P), plasma membrane signalling is regulated by cell-surface endopeptidases (e.g. neprilysin) that degrade extracellular neuropeptides, and receptor interaction with β-arrestins, which uncouple receptors from heterotrimeric G-proteins and mediate receptor endocytosis. By recruiting GPCRs, kinases and phosphatases to endocytosed GPCRs, β-arrestins assemble signalosomes that can mediate a second wave of signalling by internalized receptors. Endosomal peptidases, such as ECE-1 (endothelin-converting enzyme-1), can degrade SP in acidified endosomes, which destabilizes signalosomes and allows receptors, freed from β-arrestins, to recycle and resensitize. By disassembling signalosomes, ECE-1 terminates β-arrestin-mediated endosomal signalling. These mechanisms have been studied in model cell systems, and the relative importance of plasma membrane and endosomal signalling to complex pathophysiological processes, such as inflammation, pain and proliferation, is unclear. However, deletion or inhibition of metalloendopeptidases that control neuropeptide signalling at the plasma membrane and in endosomes has marked effects on inflammation. Neprilysin deletion exacerbates inflammation because of diminished degradation of pro-inflammatory SP. Conversely, inhibition of ECE-1 attenuates inflammation by preventing receptor recycling/resensitization, which is required for sustained pro-inflammatory signals from the plasma membrane. β-Arrestin deletion also affects inflammation because of the involvement of β-arrestins in pro-inflammatory signalling and migration of inflammatory cells. Knowledge of GPCR signalling in specific subcellular locations provides insights into pathophysiological processes, and can provide new opportunities for therapy. Selective targeting of β-arrestin-mediated endosomal signalling or of mechanisms of receptor recycling/resensitization may offer more effective and selective treatments than global targeting of cell-surface signalling.
G 蛋白偶联受体（GPCR）在质膜上的信号传递受到严格控制。对于神经肽，如 SP（P 物质），质膜信号传递受到细胞表面内肽酶（如 Neprilysin）的调节，这些内肽酶降解细胞外神经肽，以及受体与β-arrestin 的相互作用，后者将受体与异三聚体 G 蛋白分离，并介导受体内化。通过招募 GPCR、激酶和磷酸酶到内化的 GPCR 上，β-arrestin 组装信号小体，可通过内化受体介导第二波信号转导。内体肽酶，如 ECE-1（内皮素转换酶-1），可以在酸化的内体中降解 SP，从而使信号小体不稳定，并允许从β-arrestin 中释放的受体进行再循环和重新敏感化。通过拆解信号小体，ECE-1 终止了β-arrestin 介导的内体信号传递。这些机制已经在模型细胞系统中进行了研究，但在复杂的病理生理过程中，如炎症、疼痛和增殖，质膜和内体信号传递的相对重要性尚不清楚。然而，删除或抑制控制质膜和内体中神经肽信号传递的金属内肽酶，对炎症有显著影响。Neprilysin 的缺失会加剧炎症，因为促炎 SP 的降解减少。相反，ECE-1 的抑制通过阻止受体再循环/重新敏感化来减轻炎症，这是从质膜持续产生促炎信号所必需的。β-arrestin 的缺失也会影响炎症，因为β-arrestin 参与了促炎信号和炎症细胞的迁移。特定亚细胞位置的 GPCR 信号传递的知识提供了对病理生理过程的深入了解，并为治疗提供了新的机会。选择性靶向β-arrestin 介导的内体信号传递或受体再循环/重新敏感化的机制可能比靶向细胞表面信号传递提供更有效和选择性的治疗方法。
