Research summary
Seven-transmembrane (7TM) receptor signalling is reframed beyond classical heterotrimeric-G-protein activation: β-arrestins 1 and 2 act as multifunctional adaptor and transducer molecules that direct the recruitment, activation, and scaffolding of cytoplasmic signalling complexes downstream of agonist-activated receptors, providing a parallel signalling axis to the G-protein pathway [1, with the broader signalling-cascade catalog reviewed in 4]. A ternary-complex model for agonist binding at the β-adrenergic receptor was developed in which the receptor R interacts with an additional membrane component X to form a high-affinity HRX complex; computer modelling of agonist binding under varying intrinsic activity and guanine-nucleotide conditions reproduced two-affinity-state behaviour, providing the foundation for later allosteric models of GPCR activation [2]. The model was extended by showing that replacing residues 266-272 in the third intracellular loop of β2-adrenergic with the homologous α1B-adrenergic segment produced a constitutively active mutant with agonist-independent adenylyl-cyclase activation and increased agonist affinity, supplying the prototype for ligand-independent receptor activation [7]. Mechanistically, β-arrestin was identified as the adapter that couples agonist-activated β2-adrenergic receptors to c-Src family tyrosine kinases, enabling Ras-dependent MAP-kinase activation; β-arrestin 1 mutants defective in either c-Src binding or clathrin-coated-pit targeting acted as dominant-negative inhibitors of β2AR-mediated MAPK activation [3]. A complementary review of G-protein-coupled receptor kinases (GRKs) describes the six mammalian serine/threonine GRKs that phosphorylate agonist-bound GPCRs as the first step of receptor desensitisation, and catalogs the allosteric regulators of GRK activity: agonist-stimulated GPCRs, Gβγ subunits, phospholipid cofactors, calmodulin and recoverin, isoprenylation and palmitoylation, autophosphorylation, and protein-kinase-mediated regulation [5]. An earlier review establishes that β2-adrenergic-receptor desensitisation does not require receptor internalisation but instead arises from PKA- and βARK-mediated phosphorylation that uncouples the receptor from Gs [6].
Recent publications
- Seven-transmembrane receptorsDOI
- Transduction of Receptor Signals by ß-ArrestinsDOI
- A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor.DOI
- β-Arrestin-Dependent Formation of β 2 Adrenergic Receptor-Src Protein Kinase ComplexesDOI
- β-Arrestins and Cell SignalingDOI
- G PROTEIN–COUPLED RECEPTOR KINASESDOI
- Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase ADOI
- Cloning of the gene and cDNA for mammalian β-adrenergic receptor and homology with rhodopsinDOI
- Turning off the signal: desensitization of β‐adrenergic receptor functionDOI
- A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.DOI
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Email Robert J. Lefkowitz 6-12 months before your application deadline. Read several recent papers and reference specific work in your message. Use our how to email a Japanese professor guide for the proven email structure.
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External profiles
- ORCID: https://orcid.org/0000-0003-1472-7545
- OpenAlex: openalex.org
Profile compiled from public sources (Researchmap, OpenAlex, The University of Tokyo faculty directory). Last refreshed 2026-05. Report incorrect information.