Citations

Neuropeptide signaling requires the presence of G protein-coupled receptors (GPCRs) at the cell surface. Activated GPCRs interact with β-arrestins, which mediate receptor desensitization, endocytosis, and mitogenic signaling, and the peptide–receptor–arrestin complex is sequestered into endosomes. Although dissociation of β-arrestins is required for receptor recycling and resensitization, the critical event that initiates this process is unknown. Here we report that the agonist availability in the endosomes, controlled by the membrane metalloendopeptidase endothelin-converting enzyme 1 (ECE-1), determines stability of the peptide–receptor–arrestin complex and regulates receptor recycling and resensitization. Substance P (SP) binding to the tachykinin neurokinin 1 receptor (NK 1 R) induced membrane translocation of β-arrestins followed by trafficking of the SP–NK 1 R–β-arrestin complex to early endosomes containing ECE-1a–d. ECE-1 degraded SP in acidified endosomes, disrupting the complex; β-arrestins returned to the cytosol, and the NK 1 R, freed from β-arrestins, recycled and resensitized. An ECE-1 inhibitor, by preventing NK 1 R recycling in endothelial cells, inhibited resensitization of SP-induced inflammation. This mechanism is a general one because ECE-1 similarly regulated NK 3 R resensitization. Thus, peptide availability in endosomes, here regulated by ECE-1, determines the stability of the peptide–receptor–arrestin complex. This mechanism regulates receptor recycling, which is necessary for sustained signaling, and it may also control β-arrestin-dependent mitogenic signaling of endocytosed receptors. We propose that other endosomal enzymes and transporters may similarly control the availability of transmitters in endosomes to regulate trafficking and signaling of GPCRs. Antagonism of these endosomal processes represents a strategy for inhibiting sustained signaling of receptors, and defects may explain the tachyphylaxis of drugs that are receptor agonists.

Abstract The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.

Centrin is a calcium-binding centrosome/basal body–associated protein involved in duplication and segregation of these organelles in eukaryotes. We had shown that disruption of one of the centrin genes (centrin1) in Leishmania amastigotes resulted in failure of both basal body duplication and cytokinesis. Here, we undertook to define the role of centrin1 (TbCen1) in the duplication and segregation of basal body and its associated organelles kinetoplast and Golgi, as well as its role in cytokinesis of the procyclic form of Trypanosoma brucei by depleting its protein using RNA inhibition methodology. TbCen1-depleted cells showed significant reduction in growth compared with control cells. Morphological analysis of these cells showed they were large and pleomorphic with multiple detached flagella. Both immunofluorescence assays using organelle-specific antibodies and electron microscopic analysis showed that TbCen1-deficient cells contained multiple basal bodies, kinetoplasts, Golgi, and nuclei. These multiple organelles were, however, closely clustered together, indicating duplication without segregation in the absence of centrin. This failure in organelle segregation may be the likely cause of inhibition of cytokinesis, suggesting for the first time a new and unique role for centrin in the segregation of organelles without affecting their multiplication in the procyclic form of T. brucei.

Purpose The purposes of this study were to investigate the differences between open and arthroscopic closure of the rotator interval (RI) on glenohumeral translation and range of motion. We also sought to determine if the addition of either an open or arthroscopic RI closure increases stability of the shoulder. Methods Fourteen fresh‐frozen (10 paired) cadaveric shoulder specimens were mounted in a custom testing apparatus, and glenohumeral translation and rotation were obtained by using an optoelectric tracking system (Optotrak Certus; Northern Digital, Ontario, Canada). Specimens were randomly allocated to either open (n = 7) or arthroscopic (n = 7) plication of the RI. The following were measured first with an intact and vented specimen and subsequently after an RI closure using either open or arthroscopic techniques: (1) range of motion in neutral and 90° abduction; (2) anterior and posterior translation at neutral rotation; (3) anterior translation at 90° abduction with external rotation; and (4) posterior translation at 90° flexion with internal rotation. Results Posterior stability was not improved from the intact state by either open (1.0‐mm change) or arthroscopic (0.1‐mm change) repair. The sulcus stability was improved in the open group (5.7 mm to 2.9 mm, P = .028), but not arthroscopically (5.1 to 4.1 mm, P = .499). Neutral anterior stability was improved after open repair (7.2 to 2.6 mm, P = .018), but not arthroscopically (2.3 to 2.4 mm, P = 0.5). However, anterior stability in external rotation (ER) at 90° abduction was improved in the arthroscopic repair group (5.5 to 3.1 mm, P = .006). The mean loss of ER in neutral was greater in the open group (40.8°) versus the arthroscopic group (24.4°, P = .0038). The arthroscopic group showed an 11.7° loss of ER in 90° abduction ( P = .018) versus the open group loss of 4.8°. There were no significant differences in loss of IR in either neutral or 90° abduction. Conclusions Posterior stability was not improved by either open or arthroscopic rotator interval repair, and sulcus stability only improved with the open technique. Anterior stability in neutral was improved after open repair and in the arthroscopic repair group with the arm abducted. There was a large loss of external rotation with both techniques. Clinical Relevance This study suggests that arthroscopic RI closure adds little to the overall posterior and inferior stability of the shoulder joint, although anterior stability may be improved. There is a potentially large loss of external rotation after either repair method.