GRK specificity and Gβγ dependency determines the potential of a GPCR for arrestin-biased agonism.

G protein-coupled receptors (GPCRs) are mainly regulated by GPCR kinase (GRK) phosphorylation and subsequent β-arrestin recruitment. The ubiquitously expressed GRKs are classified into cytosolic GRK2/3 and membrane-tethered GRK5/6 subfamilies. GRK2/3 interact with activated G protein βγ-subunits to translocate to the membrane.

AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1.

Herpes simplex virus type 1 (HSV-1) is a widespread contagious pathogen, mostly causing mild symptoms on the mucosal entry side. However, systemic distribution, in particular upon reactivation of the virus in immunocompromised patients, may trigger an innate immune response and induce damage of organs. In these conditions, HSV-1 may infect vascular endothelial cells, but little is known about the regulation of HSV-1 replication and possible defense mechanisms in these cells.

A GFP-based ratiometric sensor for cellular methionine oxidation.

Methionine oxidation is a reversible post-translational protein modification, affecting protein function, and implicated in aging and degenerative diseases. The detection of accumulating methionine oxidation in living cells or organisms, however, has not been achieved. Here we introduce a genetically encoded probe for methionine oxidation (GEPMO), based on the super-folder green fluorescent protein (sfGFP), as a specific, versatile, and integrating sensor for methionine oxidation.

Publisher Correction: Internalized TSH receptors en route to the TGN induce local G-protein signaling and gene transcription.

The original version of this Article contained errors in the three equations reported in the Methods section entitled 'Statistics', as described in the accompanying Publisher Correction. These errors have been corrected in both the PDF and HTML versions of the article.

To sense or not to sense-new insights from GPCR-based and arrestin-based biosensors.

Advances in resolving crystal structures of GPCRs and their binding partners as well as improvements in live-cell microscopy and the fluorescent proteins pallet has greatly driven new ideas for designing optical sensors for the same. Sensors have been developed to monitor ligand binding as well as the ensuing ligand-induced conformational changes in GPCRs, G-proteins and arrestins. In this review we will highlight the functionality of such sensor designs starting from monitoring ligand binding to receptor activation and interaction with arrestins.

Internalization of G-protein-coupled receptors: Implication in receptor function, physiology and diseases.

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and mediate the effects of numerous hormones and neurotransmitters. The nearly 1000 GPCRs encoded by the human genome regulate virtually all physiological functions and are implicated in the pathogenesis of prevalent human diseases such as thyroid disorders, hypertension or Parkinson's disease. As a result, 30-50% of all currently prescribed drugs are targeting these receptors.

Internalized TSH receptors en route to the TGN induce local G-protein signaling and gene transcription.

A new paradigm of G-protein-coupled receptor (GPCR) signaling at intracellular sites has recently emerged, but the underlying mechanisms and functional consequences are insufficiently understood. Here, we show that upon internalization in thyroid cells, endogenous TSH receptors traffic retrogradely to the trans-Golgi network (TGN) and activate endogenous G-proteins in the retromer-coated compartment that brings them to the TGN. Receptor internalization is associated with a late cAMP/protein kinase A (PKA) response at the Golgi/TGN.

Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas.

Autonomous thyroid adenomas (ATAs) are a frequent cause of hyperthyroidism. Mutations in the genes encoding the TSH receptor (TSHR) or the Gs protein α subunit (GNAS) are found in approximately 70% of ATAs. The involvement of other genes and the pathogenesis of the remaining cases are presently unknown.

Trafficking and function of GPCRs in the endosomal compartment.

New methods based on fluorescently labeled agonists, genetically encoded fluorescent sensors, and advanced microscopy techniques, such as fluorescence resonance energy transfer (FRET) and highly inclined thin illumination (HILO), allow direct monitoring of signaling, internalization, and intracellular trafficking of G protein-coupled receptors (GPCRs) and their ligands in living cells with high temporal and spatial resolution. These methods have been essential in revealing that GPCRs can continue signaling via production of the soluble second messenger cyclic AMP after internalization into the endosomal compartment.