ArticleBMC biology2005
Engineered G protein coupled receptors reveal independent regulation of internalization, desensitization and acute signaling.
Article in BMC biology, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- ACE2 internalization induced by a SARS-CoV-2 recombinant protein is modulated by angiotensin II type 1 and bradykinin 2 receptors.Life sciences · 2022Article
- Gs/Gi Regulation of Bone Cell Differentiation: Review and Insights from Engineered Receptors.Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme · 2016Review
- Employing novel animal models in the design of clinically efficacious GPCR ligands.Current opinion in cell biology · 2014Review
- Unparalleled control of neural activity using orthogonal pharmacogenetics.ACS chemical neuroscience · 2012Review
- Mineral composition is altered by osteoblast expression of an engineered G(s)-coupled receptor.Calcified tissue international · 2011Article
- Remote control of neuronal signaling.Pharmacological reviews · 2011Review
- Constitutive Gs activation using a single-construct tetracycline-inducible expression system in embryonic stem cells and mice.Stem cell research & therapy · 2011Article
- Gs G protein-coupled receptor signaling in osteoblasts elicits age-dependent effects on bone formation.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2010Article
- Ligand-mediated activation of an engineered gs g protein-coupled receptor in osteoblasts increases trabecular bone formation.Molecular endocrinology (Baltimore, Md.) · 2010Article
- Engineered G-protein Coupled Receptors are Powerful Tools to Investigate Biological Processes and Behaviors.Frontiers in molecular neuroscience · 2009Article
- Endocytosis of the receptor-binding domain of SARS-CoV spike protein together with virus receptor ACE2.Virus research · 2008Article
- Engineering GPCR signaling pathways with RASSLs.Nature methods · 2008Review
- Conditional expression of a Gi-coupled receptor in osteoblasts results in trabecular osteopenia.Endocrinology · 2008Article
- Osteoblast expression of an engineered Gs-coupled receptor dramatically increases bone mass.Proceedings of the National Academy of Sciences of the United States of America · 2008Article
- Article
- The Anti-Cancer Effect of AImmunology, endocrine & metabolic agents in medicinal chemistry · 2007Article
- Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists.Journal of medicinal chemistry · 2006Article
Corrections and comments
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe physiological regulation of G protein-coupled receptors, through desensitization and internalization, modulates the length of the receptor signal and may influence the development of tolerance and dependence in response to chronic drug treatment. To explore the importance of receptor regulation, we engineered a series of Gi-coupled receptors that differ in signal length, degree of agonist-induced internalization, and ability to induce adenylyl cyclase superactivation. All of these receptors, based on the kappa opioid receptor, were modified to be receptors activated solely by synthetic ligands (RASSLs). This modification allows us to compare receptors that have the same ligands and effectors, but differ only in desensitization and internalization.
resultsRemoval of phosphorylation sites in the C-terminus of the RASSL resulted in a mutant that was resistant to internalization and less prone to desensitization. Replacement of the C-terminus of the RASSL with the corresponding portion of the mu opioid receptor eliminated the induction of AC superactivation, without disrupting agonist-induced desensitization or internalization. Surprisingly, removal of phosphorylation sites from this chimera resulted in a receptor that is constitutively internalized, even in the absence of agonist. However, the receptor still signals and desensitizes in response to agonist, indicating normal G-protein coupling and partial membrane expression.
conclusionsThese studies reveal that internalization, desensitization and adenylyl cyclase superactivation, all processes that decrease chronic Gi-receptor signals, are independently regulated. Furthermore, specific mutations can radically alter superactivation or internalization without affecting the efficacy of acute Gi signaling. These mutant RASSLs will be useful for further elucidating the temporal dynamics of the signaling of G protein-coupled receptors in vitro and in vivo.
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