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1.
Arthritis Res Ther ; 22(1): 5, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915059

RESUMO

OBJECTIVE: To describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy. METHODS: Retrospective data from a cohort of 55 patients with statin-induced anti-HMGCR myopathy, sequentially stratified by the presence of proximal weakness, early remission, and corticosteroid and IVIG use at treatment induction, were analyzed for optimal successful induction and maintenance of remission strategies. RESULTS: A total of 14 patients achieved remission with a corticosteroid-free induction strategy (25%). In 41 patients treated with corticosteroids, only 4 patients (10%) failed an initial triple steroid/IVIG/steroid-sparing immunosuppressant (SSI) induction strategy. Delay in treatment initiation was independently associated with lower odds of successful maintenance with immunosuppressant monotherapy (OR 0.92, 95% CI 0.85 to 0.97, P = 0.015). While 22 patients (40%) presented with normal strength, only 9 had normal strength at initiation of treatment. CONCLUSION: While corticosteroid-free treatment of anti-HMGCR myopathy is now a safe option in selected cases, initial triple steroid/IVIG/SSI was very efficacious in induction. Delays in treatment initiation and, as a corollary, delays in achieving remission decrease the odds of achieving successful maintenance with an SSI alone. Avoiding such delays, most notably in patients with normal strength, may reset the natural history of anti-HMGCR myopathy from a refractory entity to a treatable disease.

2.
Proc Natl Acad Sci U S A ; 109(17): E1028-37, 2012 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-22493236

RESUMO

G protein-coupled receptors (GPCRs) have been shown to activate the mitogen-activated protein kinases, ERK1/2, through both G protein-dependent and -independent mechanisms. Here, we describe a G protein-independent mechanism that unravels an unanticipated role for ß-arrestins. Stimulation of the V2 vasopressin receptor (V2R) in cultured cells or in vivo in rat kidney medullar collecting ducts led to the activation of ERK1/2 through the metalloproteinase-mediated shedding of a factor activating the insulin-like growth factor receptor (IGFR). This process was found to be both Src- and ß-arrestin-dependent. Whereas Src was found to act upstream of the metalloproteinase activation and be required for the release of the IGFR-activating factor, ß-arrestins were found to act downstream of the IGFR transactivation. Unexpectedly, the engagement of ß-arrestins by the IGFR but not by the V2R was needed to promote the vasopressin-stimulated ERK1/2 activation, indicating that a pool of ß-arrestins distinct from those ß-arrestins recruited to the V2R acts downstream of the receptor tyrosine kinase to activate ERK1/2. Such a dual site of action for ß-arrestins helps explain the pleiotropic actions of this scaffolding protein. Given the role that V2R-stimulated ERK1/2 plays in kidney cell proliferation, this transactivation mechanism may have important implications for renal pathophysiology. Still, the role of ß-arrestins downstream of a transactivation event is not limited to the V2R, because we observed a similar involvement for an unrelated GPCR (the platelet-activating factor receptor), indicating that it may be a general mechanism shared among GPCRs.


Assuntos
Arrestinas/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptores de Somatomedina/metabolismo , Receptores de Vasopressinas/metabolismo , Ativação Transcricional , Animais , Células Cultivadas , Ativação Enzimática , Medula Renal/citologia , Medula Renal/metabolismo , Ratos , Receptores de Somatomedina/genética , beta-Arrestinas
3.
Mol Pharmacol ; 77(5): 836-45, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20159941

RESUMO

Substitution of arginine-137 of the vasopressin type 2 receptor (V2R) for histidine (R137H-V2R) leads to nephrogenic diabetes insipidus (NDI), whereas substitution of the same residue to cysteine or leucine (R137C/L-V2R) causes the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). These two diseases have opposite clinical outcomes. Still, the three mutant receptors were shown to share constitutive beta-arrestin recruitment and endocytosis, resistance to vasopressin-stimulated cAMP production and mitogen-activated protein kinase activation, and compromised cell surface targeting, raising questions about the contribution of these phenomenons to the diseases and their potential treatments. Blocking endocytosis exacerbated the elevated basal cAMP levels promoted by R137C/L-V2R but not the cAMP production elicited by R137H-V2R, demonstrating that substitution of Arg137 to Cys/Leu, but not His, leads to constitutive V2R-stimulated cAMP accumulation that most likely underlies NSIAD. The constitutively elevated endocytosis of R137C/L-V2R attenuates the signaling and most likely reduces the severity of NSIAD, whereas the elevated endocytosis of R137H-V2R probably contributes to NDI. The constitutive signaling of R137C/L-V2R was not inhibited by treatment with the V2R inverse agonist satavaptan (SR121463). In contrast, owing to its pharmacological chaperone property, SR121463 increased the R137C/L-V2R maturation and cell surface targeting, leading to a further increase in basal cAMP production, thus disqualifying it as a potential treatment for patients with R137C/L-V2R-induced NSIAD. However, vasopressin was found to promote beta-arrestin/AP-2-dependent internalization of R137H/C/L-V2R beyond their already elevated endocytosis levels, raising the possibility that vasopressin could have a therapeutic value for patients with R137C/L-V2R-induced NSIAD by reducing steady-state surface receptor levels, thus lowering basal cAMP production.


Assuntos
Diabetes Insípido Nefrogênico/genética , Síndrome de Secreção Inadequada de HAD/genética , Receptores de Vasopressinas/genética , Substituição de Aminoácidos , Arginina/genética , Arginina Vasopressina/farmacologia , Arrestinas/genética , Linhagem Celular , AMP Cíclico/metabolismo , Histidina/genética , Humanos , Rim , Microscopia de Fluorescência , Mutagênese , Mutação , Plasmídeos , Transfecção , beta-Arrestinas
4.
Mol Pharmacol ; 74(1): 162-72, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18403719

RESUMO

In recent years, several studies have demonstrated that different ligands can have distinct efficacy profiles toward various signaling pathways through a unique receptor. For example, beta1-adrenergic compounds that are inverse agonists toward the adenylyl cyclase (AC) can display agonist activity for the mitogen-activated protein kinase (MAPK) pathway. Such a phenomenon, often termed functional selectivity, has now been clearly established for many G protein-coupled receptors when considering distinct signaling output. However, the possibility that ligands could selectively engage distinct effectors to activate a single signaling output by promoting specific receptor conformations has not been extensively examined. Here, we took advantage of the fact that isoproterenol, bucindolol and propranolol (full, partial, and inverse agonists for the AC pathway, respectively) all activate MAPK through the beta1-adrenergic receptor (beta1AR) to probe such conformational-biased signaling. Although the three compounds stimulated MAPK in a src-dependent manner, isoproterenol acted through both Galpha(i)betagamma- and G protein-independent pathways, whereas bucindolol and propranolol promoted MAPK activation through the G protein-independent pathway only. The existence of such distinct signaling cascades linking beta1AR to MAPK activation was correlated with ligand-specific conformational rearrangements of receptor/G protein complexes measured by bioluminescence resonance energy transfer. Taken together, our data indicate that discrete local conformational changes can selectively promote the recruitment of distinct proximal signaling partners that can engage distinct signaling outputs and/or converge on the same signaling output.


Assuntos
Proteínas Quinases Ativadas por Mitógeno/química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Conformação Proteica , Receptores Adrenérgicos beta 1/metabolismo , Transdução de Sinais , Linhagem Celular , AMP Cíclico/biossíntese , Hemaglutininas/metabolismo , Humanos , Rim/citologia , Ligantes , Fosforilação , Receptores Adrenérgicos beta 1/química , Transfecção
5.
Trends Pharmacol Sci ; 28(8): 423-30, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17659355

RESUMO

The efficacy of a drug is generally determined by the drug's ability to promote a quantifiable biological response. In the context of the classical receptor-occupancy theory, the efficacy is considered an intrinsic property of the ligand/receptor pair, and it is often assumed to be the same for all the responses evoked by this pair. The recognition that a single receptor can engage different signalling pathways and that various drugs binding to this receptor might differentially influence each of these pathways led to the reassessment of the efficacy concept. Of particular notice is the fact that ligands that behave as agonists toward a given signalling pathway can act, through the same receptor, as antagonists or even inverse agonists on a different pathway in the same cell. These observations, variously referred to as 'ligand-directed trafficking of receptor signalling' (LDTRS), 'functional selectivity', 'biased agonism', 'ligand-biased efficacy', 'collateral efficacy' or 'pluridimensional efficacy', have important implications for the molecular definition of efficacy and the process of drug discovery.


Assuntos
Desenho de Drogas , Preparações Farmacêuticas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Humanos , Modelos Biológicos , Preparações Farmacêuticas/administração & dosagem , Ligação Proteica , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
6.
Cell Signal ; 19(1): 32-41, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16857342

RESUMO

The V2 vasopressin receptor (V2R) activates the mitogen activated protein kinases (MAPK) ERK1/2 through a mechanism involving the scaffolding protein beta arrestin. Here we report that this activating pathway is independent of G alpha s, G alpha i, G alpha q or G betagamma and that the V2R-mediated activation of G alpha s inhibits ERK1/2 activity in a cAMP/PKA-dependent manner. In the HEK293 cells studied, the beta arrestin-promoted activation was found to dominate over the PKA-mediated inhibition of the pathway, leading to a strong vasopressin-stimulated ERK1/2 activation. Despite the strong MAPK activation and in contrast with other GPCR, V2R did not induce any significant increase in DNA synthesis, consistent with the notion that the stable interaction between V2R and beta arrestin prevents signal propagation to the nucleus. Beta arrestin was found to be essential for the ERK1/2 activation, indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues. Based on the use of selective pharmacological inhibitors, dominant negative mutants and siRNA, we conclude that the beta arrestin-dependent activation of ERK1/2 by the V2R involves c-Src and a metalloproteinase-dependent trans-activation event. These findings demonstrate that beta arrestin is a genuine signalling initiator that can, on its own, engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand.


Assuntos
Proteínas Heterotriméricas de Ligação ao GTP/fisiologia , Proteína Quinase 1 Ativada por Mitógeno/fisiologia , Proteína Quinase 3 Ativada por Mitógeno/fisiologia , Receptores de Vasopressinas/fisiologia , Animais , Arrestinas/metabolismo , Linhagem Celular , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ativação Enzimática , Humanos , Metaloproteinases da Matriz/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Ativação Transcricional , beta-Arrestinas , Quinases da Família src
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