The impact of RGS and other G-protein regulatory proteins on Gα_i-mediated signaling in immunity

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• 作者：John H. Kehrl ; ^{jkehrl@niaid.nih.gov" class="auth_mail" title="E-mail the corresponding author}
• 关键词：G-protein ; RGS proteins ; Chemokine receptors ; Sphingosine 1-phosphate ; Cell trafficking
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：114
• 期：Complete
• 页码：40-52
• 全文大小：1372 K

文摘

Leukocyte chemoattractant receptors are members of the G-protein coupled receptor (GPCR) family. Signaling downstream of these receptors directs the localization, positioning and homeostatic trafficking of leukocytes; as well as their recruitment to, and their retention at, inflammatory sites. Ligand induced changes in the molecular conformation of chemoattractant receptors results in the engagement of heterotrimeric G-proteins, which promotes α subunits to undergo GTP/GDP exchange. This results in the functional release of βγ subunits from the heterotrimers, thereby activating downstream effector molecules, which initiate leukocyte polarization, gradient sensing, and directional migration. Pertussis toxin ADP ribosylates Gα_i subunits and prevents chemoattractant receptors from triggering Gα_i nucleotide exchange. The use of pertussis toxin revealed the essential importance of Gα_i subunit nucleotide exchange for chemoattractant receptor signaling. More recent studies have identified a range of regulatory mechanisms that target these receptors and their associated heterotrimeric G-proteins, thereby helping to control the magnitude, kinetics, and duration of signaling. A failure in these regulatory pathways can lead to impaired receptor signaling and immunopathology. The analysis of mice with targeted deletions of Gα_i isoforms as well as some of these G-protein regulatory proteins is providing insights into their roles in chemoattractant receptor signaling.