Bahouth Suleiman W, Nooh Mohammed M
Department of Pharmacology, The University of Tennessee Health Sciences Center, 71 S. Manassas, Memphis, TN 38103, USA.
Department of Biochemistry, Faculty of Pharmacy Cairo University, Kasr El-Aini St., Cairo 11562, Egypt.
Cell Signal. 2017 Aug;36:42-55. doi: 10.1016/j.cellsig.2017.04.015. Epub 2017 Apr 24.
Proper signaling by G protein coupled receptors (GPCR) is dependent on the specific repertoire of transducing, enzymatic and regulatory kinases and phosphatases that shape its signaling output. Activation and signaling of the GPCR through its cognate G protein is impacted by G protein-coupled receptor kinase (GRK)-imprinted "barcodes" that recruit β-arrestins to regulate subsequent desensitization, biased signaling and endocytosis of the GPCR. The outcome of agonist-internalized GPCR in endosomes is also regulated by sequence motifs or "barcodes" within the GPCR that mediate its recycling to the plasma membrane or retention and eventual degradation as well as its subsequent signaling in endosomes. Given the vast number of diverse sequences in GPCR, several trafficking mechanisms for endosomal GPCR have been described. The majority of recycling GPCR, are sorted out of endosomes in a "sequence-dependent pathway" anchored around a type-1 PDZ-binding module found in their C-tails. For a subset of these GPCR, a second "barcode" imprinted onto specific GPCR serine/threonine residues by compartmentalized kinase networks was required for their efficient recycling through the "sequence-dependent pathway". Mutating the serine/threonine residues involved, produced dramatic effects on GPCR trafficking, indicating that they played a major role in setting the trafficking itinerary of these GPCR. While endosomal SNX27, retromer/WASH complexes and actin were required for efficient sorting and budding of all these GPCR, additional proteins were required for GPCR sorting via the second "barcode". Here we will review recent developments in GPCR trafficking in general and the human β-adrenergic receptor in particular across the various trafficking roadmaps. In addition, we will discuss the role of GPCR trafficking in regulating endosomal GPCR signaling, which promote biochemical and physiological effects that are distinct from those generated by the GPCR signal transduction pathway in membranes.
G蛋白偶联受体（GPCR）的正常信号传导依赖于转导、酶促和调节激酶及磷酸酶的特定组合，这些因素塑造了其信号输出。GPCR通过其同源G蛋白的激活和信号传导受到G蛋白偶联受体激酶（GRK）印记的“条形码”影响，这些“条形码”招募β-抑制蛋白来调节GPCR随后的脱敏、偏向信号传导和内吞作用。内体中激动剂内化的GPCR的结果也受到GPCR内序列基序或“条形码”的调节，这些基序介导其循环回到质膜或滞留并最终降解，以及其随后在内体中的信号传导。鉴于GPCR中存在大量不同的序列，已经描述了几种内体GPCR的转运机制。大多数循环的GPCR通过其C末端发现的1型PDZ结合模块周围的“序列依赖性途径”从内体中分拣出来。对于这些GPCR的一个子集，通过“序列依赖性途径”进行有效循环需要由区室化激酶网络印记在特定GPCR丝氨酸/苏氨酸残基上的第二个“条形码”。突变所涉及的丝氨酸/苏氨酸残基对GPCR转运产生了显著影响，表明它们在设定这些GPCR的转运行程中起主要作用。虽然内体SNX27、逆转录复合物/WASH复合物和肌动蛋白是所有这些GPCR有效分拣和出芽所必需的，但通过第二个“条形码”进行GPCR分拣还需要其他蛋白质。在这里，我们将综述GPCR转运的最新进展，特别是人类β-肾上腺素能受体在各种转运路线图中的进展。此外，我们将讨论GPCR转运在调节内体GPCR信号传导中的作用，这促进了与膜中GPCR信号转导途径产生的生化和生理效应不同的效应。
