21 research outputs found
Recommended from our members
The role of ubiquitination and hepatocyte growth factor-regulated tyrosine kinase substrate in the degradation of the adrenomedullin type I receptor
Calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 2 (RAMP2) comprise a receptor for adrenomedullin (AM). Although it is known that AM induces internalization of CLR•RAMP2, little is known about the molecular mechanisms that regulate the trafficking of CLR•RAMP2. Using HEK and HMEC-1 cells, we observed that AM-induced activation of CLR•RAMP2 promoted ubiquitination of CLR. A mutant (CLRΔ9KR), lacking all intracellular lysine residues was functional and trafficked similar to the wild-type receptor, but was not ubiquitinated. Degradation of CLR•RAMP2 and CLRΔ9KR•RAMP2 was not dependent on the duration of AM stimulation or ubiquitination and occurred via a mechanism that was partially prevented by peptidase inhibitors. Degradation of CLR•RAMP2 was sensitive to overexpression of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), but not to HRS knockdown, whereas CLRΔ9KR•RAMP2 degradation was unaffected. Overexpression, but not knockdown of HRS, promoted hyperubiquitination of CLR under basal conditions. Thus, we propose a role for ubiquitin and HRS in the regulation of AM-induced degradation of CLR•RAMP2
Supplementary Material for: Outcomes of Endobronchial Valve Treatment Based on the Precise Criteria of an Endobronchial Catheter for Detection of Collateral Ventilation under Spontaneous Breathing
<p><b><i>Background:</i></b> Endoscopic lung volume reduction with valves is a valid therapeutic option for COPD patients with severe emphysema. The exclusion of interlobar collateral ventilation (CV) is an important predictor of clinical success. <b><i>Objectives:</i></b> Recently, a catheter-based endobronchial in vivo measurement system (Chartis, Pulmonx, USA) has become routine in the clinical evaluation of CV status in target lobes, but the criteria for phenotyping CV by Chartis evaluation have not yet been defined. We asked the questions, how many phenotypes can be identified using Chartis, what are the exact criteria to distinguish them, and how do the Chartis phenotypes respond to valve insertionκ <b><i>Methods:</i></b> In a retrospective study, 406 Chartis assessments of 166 patients with severe COPD were analyzed. Four Chartis phenotypes, CV positive (CV+), CV negative (CV-), low flow (LF) and low plateau were identified. Fifty-two patients without CV were treated with valves and followed for 3 months. <b><i>Results:</i></b> The Chartis phenotypes were discriminated with respect to decline in expiratory peak flow, increase in resistance index and change in total exhaled volume after 1, 2, 3, 4 and 5 min of measurement time (p < 0.0001, ANOVA), and the cutoff criteria were defined accordingly. To examine the application of these phenotyping criteria, students applied them to 100 Chartis assessments, and they demonstrated almost perfect inter- and intraobserver agreements (κ > 0.9). Compared to baseline, CV- and LF patients with ipsilateral CV- lobe showed an improvement in FEV<sub>1</sub> (p < 0.05), vital capacity (p < 0.05) and target lobe volume reduction (p < 0.005) after valve insertion. <b><i>Conclusion:</i></b> This study describes the most prevalent Chartis phenotypes.</p