The Regulator of G Protein Signaling Homologous Domain of G Protein-Coupled Receptor Kinase 2 Mediates Short-Term Desensitization of β3-Adrenergic Receptor
G protein coupled receptor (GPCR) kinases (GRKs) are key regulators of GPCR signaling. Canonical mechanism of GPCR desensitization involves receptor phosphorylation by GRKs followed by arrestin recruitment and uncoupling from heterotrimeric G protein. Although β3-adrenergic receptor (β3AR) lacks phosphorylation sites by GRKs, agonist treatment proved to induce β3AR desensitization in many cell types. Here we show that GRK2 mediates short-term desensitization of β3AR by a phosphorylation independent mechanism but mediated by its domain homologous to the regulator of G protein signaling (RGS). HEK293T cells overexpressing human β3AR presented a short-term desensitization of cAMP response stimulated by the β3AR agonist, BRL37344, and not by forskolin. We found that β3AR desensitization was higher in cells co-transfected with GRK2. Similarly, overexpression of the RGS homology domain but not kinase domain of GRK2 increased β3AR desensitization. Consistently, stimulation of β3AR increased interaction between GRK2 and Gαs subunit. Furthermore, in rat cardiomyocytes endogenously expressing β3AR, transfection with dominant negative mutant of RH domain of GRK2 (GRK2/D110A) increased cAMP response to BRL37344 and inhibited receptor desensitization. We expect our study to be a starting point for more sophisticated characterization of the consequences of GRK2 mediated desensitization of the β3AR in heart function and disease.
CONCLUSION: Prevalence of antibiotic use was high not only versus other hospitals in the region but globally including Africa, coupled with significant evidence of sub-optimal prescribing. Swift action is needed to improve future prescribing to reduce AMR. One or two areas should initially be targeted for quality improvement including development of local guidelines, documentation of antibiotic indications and/or stop/review dates. PMID: 33034234 [PubMed - as supplied by publisher]
Authors: Rombauts A, Abelenda-Alonso G, Cuervo G, Gudiol C, Carratalà J Abstract INTRODUCTION: Despite adequate antibiotic coverage, community-acquired pneumonia (CAP) remains a leading cause of hospitalization and mortality worldwide. It induces both a local pulmonary and a systemic inflammatory response, particularly significant in severe cases. The intensity of the dysregulated host response varies from patient to patient and has a negative impact on survival and other outcomes. AREAS COVERED: This comprehensive review summarizes the pathophysiological aspects of the inflammatory response in CAP, brie...
Authors: Hammerschlag MR, Sharma R Abstract INTRODUCTION: Azithromycin was recommended as the first-line therapeutic regimen for treatment of genital infections in men and women by the Centers for Disease Control in 1998. A series of studies of azithromycin for treatment of rectal chlamydial infection in men who have sex with men (MSM) found that azithromycin was significantly less effective than doxycycline. AREAS COVERED: Literature on treatment of rectal C. trachomatis from 2000 through May 2020 was searched using PubMed. Retrospective and observational studies were identified documenting the frequency and t...
Authors: Reissier S, Cattoir V Abstract INTRODUCTION: Streptogramins (pristinamycin and quinupristin-dalfopristin) can be interesting options for the treatment of infections due to Gram-positive cocci, especially multidrug-resistant isolates. AREAS COVERED: This review provides an updated overview on structural and activity characteristics, mechanisms of action and resistance, pharmacokinetic/pharmacodynamic and clinical use of streptogramins. EXPERT OPINION: The streptogramin antibiotics act by inhibition of the bacterial protein synthesis. They are composed of two chemically distinct compounds, namely typ...
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