Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA.
Br J Pharmacol. 2018 Nov;175(21):4026-4035. doi: 10.1111/bph.14023. Epub 2017 Oct 3.
Traditionally, signal transduction from GPCRs is thought to emanate from the cell surface where receptor interactions with external stimuli can be transformed into a broad range of cellular responses. However, emergent data show that numerous GPCRs are also associated with various intracellular membranes where they may couple to different signalling systems, display unique desensitization patterns and/or exhibit distinct patterns of subcellular distribution. Although many GPCRs can be activated at the cell surface and subsequently endocytosed and transported to a unique intracellular site, other intracellular GPCRs can be activated in situ either via de novo ligand synthesis, diffusion of permeable ligands or active transport of nonpermeable ligands. Current findings reinforce the notion that intracellular GPCRs play a dynamic role in various biological functions including learning and memory, contractility and angiogenesis. As new intracellular GPCR roles are defined, the need to selectively tailor agonists and/or antagonists to both intracellular and cell surface receptors may lead to the development of more effective therapeutic tools.
This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.
传统上，GPCR 的信号转导被认为源自细胞表面，在那里受体与外部刺激的相互作用可以转化为广泛的细胞反应。然而，新出现的数据表明，许多 GPCR 也与各种细胞内膜相关联，在那里它们可以与不同的信号系统偶联，表现出独特的脱敏模式和/或表现出独特的亚细胞分布模式。尽管许多 GPCR 可以在细胞表面被激活，随后内吞并转运到独特的细胞内位置，但其他细胞内 GPCR 可以通过从头合成配体、可渗透配体的扩散或非渗透配体的主动转运原位激活。目前的发现强化了这样一种观点，即细胞内 GPCR 在包括学习和记忆、收缩性和血管生成在内的各种生物学功能中发挥着动态作用。随着新的细胞内 GPCR 作用被定义，需要有选择性地将激动剂和/或拮抗剂应用于细胞内和细胞表面受体，这可能会导致更有效的治疗工具的发展。
本文是关于 GPCR 分子药理学的专题部分的一部分。要查看本节中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc/。
