OBJECTIVETo report the events during and after radical cystectomy and urinary diversion for bladder cancer, in terms of major and minor complications, comparing a minimal with an extended lymphadenectomy, as more lymph nodes obtained during radical cystectomy may improve staging and thus the outcome.PATIENTS AND METHODSWe reviewed 92 consecutive patients who underwent radical cystectomy from March 1998 to February 2002; 46 had a minimal (group A) and 46 an extended lymphadenectomy (group B). Cases were selected according to the American Society of Anesthesiologists classification, only including those graded 2 or 3. We specifically evaluated the incidence and type of complications within 30 days after surgery.RESULTSBecause of extending the lymphadenectomy the operative duration was a median of 63 min longer in group B (P < 0.01). Complications requiring surgical interventions occurred in four (9%) patients in group A and five (11%) in group B (P = 0.28). Complications requiring no surgical intervention were also similar in both groups. Three patients died, two in group A and one in group B (P = 0.57).CONCLUSIONExtended lymphadenectomy in radical cystectomy does not increase the morbidity within 30 days of surgery.
AT angiotensin receptor (ATR), a prototypical G protein-coupled receptor (GPCR), is the main receptor, which mediates the effects of the renin-angiotensin system (RAS). ATR plays a crucial role in the regulation of blood pressure and salt-water homeostasis, and in the development of pathological conditions, such as hypertension, heart failure, cardiovascular remodeling, renal fibrosis, inflammation, and metabolic disorders. Stimulation of ATR leads to pleiotropic signal transduction pathways generating arrays of complex cellular responses. Growing amount of evidence shows that ATR is a versatile GPCR, which has multiple unique faces with distinct conformations and signaling properties providing new opportunities for functionally selective pharmacological targeting of the receptor. Biased ligands of ATR have been developed to selectively activate the β-arrestin pathway, which may have therapeutic benefits compared to the conventional angiotensin converting enzyme inhibitors and angiotensin receptor blockers. In this review, we provide a summary about the most recent findings and novel aspects of the ATR function, signaling, regulation, dimerization or oligomerization and its cross-talk with other receptors, including epidermal growth factor (EGF) receptor, adrenergic receptors and CB cannabinoid receptor. Better understanding of the mechanisms and structural aspects of ATR activation and cross-talk can lead to the development of novel type of drugs for the treatment of cardiovascular and other diseases.
The role of the highly conserved 'DRY' motif in the signaling of the CB 1 cannabinoid receptor (CB 1 R) was investigated by inducing single-, double-, and triple-alanine mutations into this site of the receptor. We found that the CB 1 R-R3.50A mutant displays a partial decrease in its ability to activate heterotrimeric G o proteins (w80% of WT CB 1 R (CB 1 R-WT)). Moreover, this mutant showed an enhanced basal b-arrestin2 (b-arr2) recruitment. More strikingly, the double-mutant CB 1 R-D3.49A/R3.50A was biased toward b-arrs, as it gained a robustly increased b-arr1 and b-arr2 recruitment ability compared with the WT receptor, while its G-protein activation was decreased. In contrast, the double-mutant CB 1 R-R3.50A/Y3.51A proved to be G-protein-biased, as it was practically unable to recruit b-arrs in response to agonist stimulus, while still activating G-proteins, although at a reduced level (w70% of CB 1 R-WT). Agonist-induced ERK1/2 activation of the CB 1 R mutants showed a good correlation with their b-arr recruitment ability but not with their G-protein activation or inhibition of cAMP accumulation. Our results suggest that G-protein activation and b-arr binding of the CB 1 R are mediated by distinct receptor conformations, and the conserved 'DRY' motif plays different roles in the stabilization of these conformations, thus mediating both G-protein-and b-arr-mediated functions of CB 1 R.
β-arrestins are key regulators and signal transducers of G protein-coupled receptors (GPCRs). The interaction between receptorsand β-arrestins is generally believed to require both receptor activity and phosphorylation by GPCR kinases. In this study, we investigated whether β-arrestins are able to bind second messenger kinase-phosphorylated, but inactive receptors as well. Since heterologous phosphorylation is a common phenomenon among GPCRs, this mode of β-arrestin activation may represent a novel mechanism of signal transduction and receptor cross-talk.Here we demonstrate that activation of protein kinase C (PKC) by phorbol myristate acetate, G q/11-coupled GPCR or epidermal growth factor receptor stimulation promotes β-arrestin2 recruitment to unliganded AT1 angiotensin receptor (AT1R). We found that this interaction depends on the stability lock, a structure responsible for the sustained binding between GPCRs and β-arrestins, formed by phosphorylated serine-threonine clusters in the receptor's C-terminus and two conserved phosphate-binding lysines in the β-arrestin2 Ndomain. Using improved FlAsH-based β-arrestin2 conformational biosensors, we also show that the stability lock not only stabilizes the receptor-β-arrestin interaction, but also governs the structural rearrangements within β-arrestins. Furthermore, we found that β-arrestin2 binds to PKC-phosphorylated AT1R in a distinct active conformation, which triggers MAPK recruitment and receptor internalization. Our results provide new insights into the activation of β-arrestins and reveal their novel role in receptor cross-talk.The family of G protein-coupled receptors (GPCRs) consists of ~800 members in humans and about 30% of modern drugs target these molecules (1). GPCRs respond to a wide variety of endogenous ligands, including hormones, neurotransmitters, and lipids. Despite their huge diversity, the signal transduction mechanisms of GPCRs share several common features: agonist binding is followed by the activation of a relatively small number of heterotrimeric G proteins, which initiate complex intracellular signaling cascades. Receptor responsiveness to further stimulation is attenuated by a multistep process, called desensitization (2). In case of homologous desensitization, active GPCRs are phosphorylated by GPCR kinases (GRKs) followed by the recruitment of β-arrestin proteins (β-arrestin1 and JBC C o n f i d e n t i a lHeterologous regulation of inactive receptors via β-arrestin 2 β-arrestin2, also known as arrestin-2 and arrestin-3, respectively). β-arrestins uncouple the receptors from G proteins and initiate receptor internalization (3), thereby serving as the key regulators of GPCRs' function. In contrast, heterologous desensitization is mediated by second-messenger activated kinases, such as protein kinase C (PKC), which can phosphorylate active and inactive receptors. Heterologous desensitization was originally thought to be independent of β-arrestins, however, some data have challenged this concept (4-6). In addition to their rol...
Biased agonism on the type I angiotensin receptor (AT 1 -R) can achieve different outcomes via activation of G protein-dependent and -independent cellular responses. In this study, we investigated whether the biased activation of AT 1 -R can lead to different regulation and intracellular processing of the receptor. We analyzed b-arrestin binding, endocytosis, and subsequent trafficking steps, such as early and late phases of recycling of AT 1 -R in human embryonic kidney 293 cells expressing wild-type or biased mutant receptors in response to different ligands. We used Renilla luciferase-tagged receptors and yellow fluorescent protein-tagged b-arrestin2, Rab5, Rab7, and Rab11 proteins in bioluminescence resonance energy transfer measurements to follow the fate of the receptor after stimulation. We found that not only is the signaling of the receptor different upon using selective ligands, but the fate within the cells is also determined by the type of the stimulation. b-arrestin binding and the internalization kinetics of the angiotensin II-stimulated AT 1 -R differed from those stimulated by the biased agonists. Similarly, angiotensin IIstimulated wild-type AT 1 -R showed differences compared with a biased mutant AT 1 -R (DRY/AAY AT 1 -R) with regards to b-arrestin binding and endocytosis. We found that the differences in the internalization kinetics of the receptor in response to biased agonist stimulation are due to the differences in plasma membrane phosphatidylinositol 4,5-bisphosphate depletion. Moreover, the stability of the b-arrestin binding is a major determinant of the later fate of the internalized AT 1 -R receptor.
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