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[PMID]: 28461224 [Au] Autor: Li X; Obeidat M; Zhou G; Leung JM; Tashkin D; Wise R; Connett J; Joubert P; Bossé Y; van den Berge M; Brandsma CA; Nickle DC; Hao K; Paré PD; Sin DD [Ad] Endereço: UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada. [Ti] Título: Responsiveness to Ipratropium Bromide in Male and Female Patients with Mild to Moderate Chronic Obstructive Pulmonary Disease. [So] Source: EBioMedicine;19:139-145, 2017 May. [Is] ISSN: 2352-3964 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: INTRODUCTION: Although the prevalence of chronic obstructive pulmonary disease (COPD) is similar between men and women, current evidence used to support bronchodilator therapy has been generated in therapeutic trials that have predominately enrolled male patients. Here, we determined whether there is any significant sex-related differences in FEV responses to ipratropium bromide. METHODS: Data from the Lung Health Study (n=5887; 37% females) were used to determine changes in FEV with ipratropium or placebo in male and female subjects with mild to moderate COPD over 5years. Lung Expression Quantitative Trait Loci (eQTL) dataset was used to determine whether there were any sex-related differences in gene expression for muscarinic (M2 and M3) receptors in lungs of male and female patients. RESULTS: After 4months, ipratropium therapy increased FEV by 6.0% in female and 2.9% in male subjects from baseline values (p=2.42×10 ). This effect was modified by body mass index (BMI) such that the biggest improvements in FEV with ipratropium were observed in thin female subjects (p for BMI∗sex interaction=0.044). The sex-related changes in FEV related to ipratropium persisted for 2years (p=0.0134). Female compared with male lungs had greater gene expression for M3 relative to M2 receptors (p=6.86×10 ). CONCLUSION: Ipratropium induces a larger bronchodilator response in female than in male patients and the benefits are particularly notable in non-obese females. Female lungs have greater gene expression for the M3 muscarinic receptor relative to M2 receptors than male lungs. Female patients are thus more likely to benefit from ipratropium than male COPD patients. [Mh] Termos MeSH primário: Broncodilatadores/uso terapêutico Antagonistas Colinérgicos/uso terapêutico Ipratrópio/uso terapêutico Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico [Mh] Termos MeSH secundário: Adulto Índice de Massa Corporal Feminino Volume Expiratório Forçado Expressão Gênica Seres Humanos Masculino Meia-Idade Doença Pulmonar Obstrutiva Crônica/genética Doença Pulmonar Obstrutiva Crônica/fisiopatologia Receptor Muscarínico M2/genética Receptor Muscarínico M3/genética Caracteres Sexuais Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL [Nm] Nome de substância: 0 (Bronchodilator Agents); 0 (Cholinergic Antagonists); 0 (Receptor, Muscarinic M2); 0 (Receptor, Muscarinic M3); GR88G0I6UL (Ipratropium) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE

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[PMID]: 29176315 [Au] Autor: Liu Q; Luo D; Yang T; Liao B; Li H; Wang KJ [Ti] Título: Protective Effects of Antimuscarinics on the Bladder Remodeling After Bladder Outlet Obstruction. [So] Source: Cell Physiol Biochem;44(3):907-919, 2017. [Is] ISSN: 1421-9778 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: BACKGROUND/AIMS: Overactive bladder associated with bladder outlet obstruction (BOO) is a highly prevalent condition, which is usually treated with antimuscarinics. However, the potential effects of antimuscarinics on the structure and function of bladder have not been investigated thus far. METHODS: Sprague-Dawley(R) rats accepted bladder neck obstruction surgery or sham surgery, and then received treatment of three different antimuscarinics (Solifenacin, Darifenacin, and Tolterodine) or vehicle. After 3, 6 and 12 weeks, the bladder function and structure were measured. The effect of antimuscarinics on cellular alteration in vitro was observed under mechanical stimulation. Bladder morphology were examined by immunohistochemistry, and the bladder function were investigated by cystometry and strip contractility test. The expression of muscarinic receptors and inflammatory cytokines were measured by PCR and Western blotting. RESULTS: Here we demonstrate, both in vitro and in vivo, that antimuscarinics are protective regulators for the bladder structure and function. Antimuscarinics decrease the weight of bladders with BOO. Antimuscarinics improve the voiding parameter and enhance the contraction of bladder smooth muscle. The results also show that antimuscarinics inhibit the proliferation of bladder smooth muscle cells both in vivo and in vitro, it can reduce the collagen deposition and inflammatory cytokines in bladders with BOO. During this process, the expression of M2 and M3 receptors was altered by antimuscarinics. CONCLUSION: Antimuscarinics could reverse the structural and functional changes of BOO bladder wall at cellular and tissue level, and the alteration of M2 and M3 receptors may be involved in this biological process. [Mh] Termos MeSH primário: Antagonistas Muscarínicos/farmacologia Substâncias Protetoras/farmacologia Bexiga Urinária/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Benzofuranos/farmacologia Linhagem Celular Proliferação Celular/efeitos dos fármacos Colágeno/metabolismo Citocinas/metabolismo Modelos Animais de Doenças Feminino Seres Humanos Imuno-Histoquímica Contração Muscular/efeitos dos fármacos Miócitos de Músculo Liso/citologia Miócitos de Músculo Liso/efeitos dos fármacos Miócitos de Músculo Liso/metabolismo Cloreto de Potássio/farmacologia Antígeno Nuclear de Célula em Proliferação/metabolismo Pirrolidinas/farmacologia Ratos Ratos Sprague-Dawley Receptor Muscarínico M3/metabolismo Tartarato de Tolterodina/farmacologia Bexiga Urinária/metabolismo Bexiga Urinária/patologia Obstrução do Colo da Bexiga Urinária/metabolismo Obstrução do Colo da Bexiga Urinária/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Benzofurans); 0 (Cytokines); 0 (Muscarinic Antagonists); 0 (Proliferating Cell Nuclear Antigen); 0 (Protective Agents); 0 (Pyrrolidines); 0 (Receptor, Muscarinic M3); 5T619TQR3R (Tolterodine Tartrate); 660YQ98I10 (Potassium Chloride); 9007-34-5 (Collagen); APG9819VLM (darifenacin) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180118 [Lr] Data última revisão: 180118 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171128 [St] Status: MEDLINE [do] DOI: 10.1159/000485358

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[PMID]: 28893976 [Au] Autor: Pronin AN; Wang Q; Slepak VZ [Ad] Endereço: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida vslepak@med.miami.edu a.pronin@med.miami.edu. [Ti] Título: Teaching an Old Drug New Tricks: Agonism, Antagonism, and Biased Signaling of Pilocarpine through M3 Muscarinic Acetylcholine Receptor. [So] Source: Mol Pharmacol;92(5):601-612, 2017 Nov. [Is] ISSN: 1521-0111 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Pilocarpine is a prototypical drug used to treat glaucoma and dry mouth and is classified as either a full or partial muscarinic agonist. Here, we report several unexpected results pertaining to its interaction with muscarinic M3 receptor (M3R). We found that pilocarpine was 1000 times less potent in stimulating mouse-eye pupil constriction than muscarinic agonists oxotremorin-M (Oxo-M) or carbachol (CCh), although all three ligands have similar values for M3R. In contrast to CCh or Oxo-M, pilocarpine does not induce Ca mobilization via endogenous M3R in human embryonic kidney cell line 293T (HEK293T) or mouse insulinoma (MIN6) cells. Pilocarpine also fails to stimulate insulin secretion and, instead, antagonizes the insulinotropic effect of Oxo-M and CCh-induced Ca upregulation; however, in HEK293T or Chinese hamster ovary-K1 cells overexpressing M3R, pilocarpine induces Ca transients like those recorded with another cognate G protein-coupled muscarinic receptor, M1R. Stimulation of cells overexpressing M1R or M3R with CCh resulted in a similar reduction in phosphatidylinositol 4,5-bisphosphate (PIP2). In contrast to CCh, pilocarpine stimulated PIP2 hydrolysis only in cells overexpressing M1R but not M3R. Moreover, pilocarpine blocked CCh-stimulated PIP2 hydrolysis in M3R-overexpressing cells, thus, it acted as an antagonist. Pilocarpine activates extracellular regulated kinase 1/2 in MIN6 cells. The stimulatory effect on extracellular regulated kinase (ERK1/2) was blocked by the Src family kinase inhibitor PP2, indicating that the action of pilocarpine on endogenous M3R is biased toward -arrestin. Taken together, our findings show that pilocarpine can act as either an agonist or antagonist of M3R, depending on the cell type, expression level, and signaling pathway downstream of this receptor. [Mh] Termos MeSH primário: Agonistas Muscarínicos/farmacologia Antagonistas Muscarínicos/farmacologia Pilocarpina/farmacologia Receptor Muscarínico M3/agonistas Receptor Muscarínico M3/antagonistas & inibidores [Mh] Termos MeSH secundário: Animais Células CHO Cricetinae Cricetulus Relação Dose-Resposta a Droga Células HEK293 Seres Humanos Masculino Camundongos Camundongos Endogâmicos C57BL Agonistas Muscarínicos/metabolismo Antagonistas Muscarínicos/metabolismo Pilocarpina/metabolismo Receptor Muscarínico M3/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Muscarinic Agonists); 0 (Muscarinic Antagonists); 0 (Receptor, Muscarinic M3); 01MI4Q9DI3 (Pilocarpine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171102 [Lr] Data última revisão: 171102 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170913 [St] Status: MEDLINE [do] DOI: 10.1124/mol.117.109678

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[PMID]: 28797771 [Au] Autor: Lazewska D; Kaleta M; Schwed JS; Karcz T; Mogilski S; Latacz G; Olejarz A; Siwek A; Kubacka M; Lubelska A; Honkisz E; Handzlik J; Filipek B; Stark H; Kiec-Kononowicz K [Ad] Endereço: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, ul. Medyczna 9, 30-688 Kraków, Poland. Electronic address: dlazewska@cm-uj.krakow.pl. [Ti] Título: Biphenyloxy-alkyl-piperidine and azepane derivatives as histamine H receptor ligands. [So] Source: Bioorg Med Chem;25(20):5341-5354, 2017 Oct 15. [Is] ISSN: 1464-3391 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H receptor. Two series of compounds were obtained with a meta- and a para-biphenyl moiety. The alkyl chain spacer contained five and six carbon atoms. The highest affinity among all compounds was shown by 1-(6-(3-phenylphenoxy)hexyl)azepane (13) with a K value of 18nM. Two para-biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine (14; K =25nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane (16; K =34nM), classified as antagonists in a cAMP accumulation assay (IC =4 and 9nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED of 2.72mg/kg and 1.75mg/kg respectively), and showed high selectivity (hH R vs hH R>600-fold) and low toxicity (hERG inhibition: IC >1.70µM; hepatotoxicity IC >12.5µM; non-mutagenic up to 10µM). Furthermore, the metabolic stability was evaluated in vitro on human liver microsomes (HLMs) and/or rat liver microsomes (RLMs). Metabolites produced were analyzed and tentatively identified by UPLC-MS techniques. The results demonstrated easy hydroxylation of the biphenyl ring. [Mh] Termos MeSH primário: Azepinas/farmacologia Piperidinas/farmacologia Receptores Histamínicos H3/metabolismo [Mh] Termos MeSH secundário: Animais Azepinas/síntese química Azepinas/química Proliferação Celular Modelos Animais de Doenças Relação Dose-Resposta a Droga Cobaias Células HEK293 Células Hep G2 Seres Humanos Ligantes Masculino Estrutura Molecular Piperidinas/síntese química Piperidinas/química Ratos Ratos Wistar Receptor Muscarínico M3/antagonistas & inibidores Receptor Muscarínico M3/metabolismo Receptores Histamínicos H1/metabolismo Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Azepines); 0 (Ligands); 0 (Piperidines); 0 (Receptor, Muscarinic M3); 0 (Receptors, Histamine H1); 0 (Receptors, Histamine H3); 67I85E138Y (piperidine) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171107 [Lr] Data última revisão: 171107 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170812 [St] Status: MEDLINE

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[PMID]: 28750255 [Au] Autor: Namkoong E; Lee SW; Kim N; Choi Y; Park K [Ad] Endereço: Department of Physiology, School of Dentistry, Seoul National University and Dental Research Institute, Seoul, 110-749, Korea. [Ti] Título: Effect of anti-muscarinic autoantibodies on leukocyte function in Sjögren's syndrome. [So] Source: Mol Immunol;90:136-142, 2017 Oct. [Is] ISSN: 1872-9142 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Patients with primary Sjögren's syndrome, a systemic autoimmune disease, have been shown to have serum autoantibodies that react with the muscarinic acetylcholine type 3 receptor (M3R).Primary Sjögren's syndrome is a systemic autoimmune disease. Patients with primary Sjögren's syndrome have been shown to have serum autoantibodies that react with the muscarinic acetylcholine type 3 receptor (M3R). Leukopenia has been reported to be significantly more common in primary Sjögren's syndrome patients who have anti-M3R-autoantibodies in their sera. In this study, we investigated whether these anti-M3R autoantibodies have effects on M3R and MHCI expression in Jurkat T cells. Purified IgG antibodies were isolated from the serum of healthy individuals and primary Sjögren's syndrome patients. Jurkat cell line was used to represent T lymphocytes. In situ immunofluorescence confocal microscopy was used to confirm the binding reactivity of primary Sjögren's syndrome IgG antibodies to M3R. Co-immunoprecipitation and immunofluorescence results suggested a direct interaction between M3R and MHC I. Co-internalization of M3R and MHC I was observed when Jurkat cells were exposed to the primary Sjögren's syndrome IgG, but this primary Sjögren's syndrome IgG-induced co-internalization of M3R and MHC I was prevented by the presence of exogenous IFN-γ. Primary Sjögren's syndrome IgG itself did not affect the viability of Jurkat cells, but Jurkat cells exposed to primary Sjögren's syndrome IgG were observed to undergo significant cell death when co-cultured with primary Natural Killer cells. Our results suggest that anti-M3R autoantibodies in primary Sjögren's syndrome induce downregulation of plasma membrane-resident M3R and MHC class I molecules in leukocytes followed by NK cell-mediated cell death. This mechanism may explain the frequency of leukopenia occurrence in patients with primary Sjögren's syndrome. [Mh] Termos MeSH primário: Autoanticorpos/imunologia Antígenos de Histocompatibilidade Classe I/imunologia Células Matadoras Naturais/imunologia Leucócitos/imunologia Receptor Muscarínico M3/imunologia Síndrome de Sjogren/imunologia [Mh] Termos MeSH secundário: Adulto Idoso Morte Celular/imunologia Linhagem Celular Tumoral Feminino Imunofluorescência Seres Humanos Imunoglobulina G/imunologia Imunoprecipitação Células Jurkat Leucopenia/imunologia Masculino Microscopia Confocal Meia-Idade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Autoantibodies); 0 (Histocompatibility Antigens Class I); 0 (Immunoglobulin G); 0 (Receptor, Muscarinic M3) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171107 [Lr] Data última revisão: 171107 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170728 [St] Status: MEDLINE

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[PMID]: 28619712 [Au] Autor: Patel KR; Bai Y; Trieu KG; Barrios J; Ai X [Ad] Endereço: Division of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [Ti] Título: Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma. [So] Source: FASEB J;31(10):4335-4346, 2017 Oct. [Is] ISSN: 1530-6860 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Asthma often progresses into adulthood from early-life episodes of adverse environmental exposures. However, how the injury to developing lungs contributes to the pathophysiology of persistent asthma remains poorly understood. In this study, we identified an age-related mechanism along the cholinergic nerve-airway smooth muscle (ASM) axis that underlies prolonged airway hyperreactivity (AHR) in mice. We showed that ASM continued to mature until ∼3 wk after birth. Coinciding with postnatal ASM maturation, there was a critical time window for the development of ASM hypercontractility after cholinergic stimulation. We found that allergen exposure in neonatal mice, but not in adult mice, elevated the level and activity of cholinergic nerves (termed neuroplasticity). We demonstrated that cholinergic neuroplasticity is necessary for the induction of persistent AHR after neonatal exposure during rescue assays in mice deficient in neuroplasticity. In addition, early intervention with cholinergic receptor muscarinic (ChRM)-3 blocker reversed the progression of AHR in the neonatal exposure model, whereas ß2-adrenoceptor agonists had no such effect. Together, our findings demonstrate a functional relationship between cholinergic neuroplasticity and ASM contractile phenotypes that operates uniquely in early life to induce persistent AHR after allergen exposure. Targeting ChRM3 may have disease-modifying benefits in childhood asthma.-Patel, K. R., Bai, Y., Trieu, K. G., Barrios, J., Ai, X. Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma. [Mh] Termos MeSH primário: Asma/prevenção & controle Hiper-Reatividade Brônquica/metabolismo Músculo Liso/metabolismo Receptor Muscarínico M3/metabolismo [Mh] Termos MeSH secundário: Acetilcolina/metabolismo Animais Hiper-Reatividade Brônquica/diagnóstico Modelos Animais de Doenças Progressão da Doença Camundongos Knockout Contração Muscular/efeitos dos fármacos Contração Muscular/fisiologia Músculo Liso/efeitos dos fármacos Receptor Muscarínico M3/antagonistas & inibidores Sistema Respiratório/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Receptor, Muscarinic M3); N9YNS0M02X (Acetylcholine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171019 [Lr] Data última revisão: 171019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170617 [St] Status: MEDLINE [do] DOI: 10.1096/fj.201700186R

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[PMID]: 28416748 [Au] Autor: Cheng K; Shang AC; Drachenberg CB; Zhan M; Raufman JP [Ad] Endereço: Veterans Affairs Maryland Healthcare System, Baltimore VA Medical Center, Baltimore, MD, USA. [Ti] Título: Differential expression of M3 muscarinic receptors in progressive colon neoplasia and metastasis. [So] Source: Oncotarget;8(13):21106-21114, 2017 Mar 28. [Is] ISSN: 1949-2553 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: M3 muscarinic receptor (M3R) activation promotes colon cancer cell proliferation, migration, and invasion in vitro. Although over-expression of CHRM3, the gene encoding M3R, is reported in primary colon cancers, expression of M3R itself has not been studied in colon neoplasia. We compared M3R expression in normal colon to colon adenomas, and primary and metastatic colon cancers. Compared to adjacent normal colon, CHRM3 expression was increased up to 128-fold in 10 of 18 consecutive surgical cancer specimens (56%) and associated with metastatic spread (P < 0.05). To analyze M3R protein expression we interrogated 29 consecutive paraffin-embedded colon adenocarcinomas and adjacent normal colon using a specific anti-M3R antibody and immunoperoxidase staining. This revealed weak M3R expression in normal colonocytes, primarily on basolateral surfaces. In contrast, in 25 of 29 cancer tissues (86%) we observed both cytoplasmic and plasma membrane over-expression of M3R; compared to normal epithelium, mean M3R staining intensity was increased more than two-fold in colon cancer (P < 0.001). M3R staining was also increased in 22 colon adenomas compared to adjacent normal colon (P < 0.001). In contrast, M3R staining intensity was not increased in lymph node or liver metastases. These findings suggest M3R expression plays an important role in early progression and invasion of colon neoplasia but is less important once tumors have spread. [Mh] Termos MeSH primário: Neoplasias do Colo/metabolismo Neoplasias do Colo/patologia Receptores Muscarínicos/metabolismo [Mh] Termos MeSH secundário: Adenocarcinoma/metabolismo Adenocarcinoma/secundário Adenoma/metabolismo Adenoma/patologia Membrana Celular/metabolismo Proliferação Celular Colo/citologia Colo/metabolismo Seres Humanos Imuno-Histoquímica Mucosa Intestinal/citologia Mucosa Intestinal/metabolismo Neoplasias Hepáticas/metabolismo Neoplasias Hepáticas/secundário Metástase Linfática Metaloproteinase 1 da Matriz/metabolismo Invasividade Neoplásica Metástase Neoplásica RNA Mensageiro/metabolismo Reação em Cadeia da Polimerase em Tempo Real Receptor Muscarínico M3 Receptores Muscarínicos/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (CHRM3 protein, human); 0 (RNA, Messenger); 0 (Receptor, Muscarinic M3); 0 (Receptors, Muscarinic); EC 3.4.24.7 (MMP1 protein, human); EC 3.4.24.7 (Matrix Metalloproteinase 1) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170419 [St] Status: MEDLINE [do] DOI: 10.18632/oncotarget.15500

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[PMID]: 28148778 [Au] Autor: Montenegro MF; Cabezas-Herrera J; Campoy FJ; Muñoz-Delgado E; Vidal CJ [Ad] Endereço: Departamento de Bioquímica y Biología Molecular-A, Instituto Murciano de Investigación Biosanitaria (IMIB), Universidad de Murcia, Regional Campus of International Excellence "Campus Mare Nostrum," Murcia, Spain; and. [Ti] Título: Lipid rafts of mouse liver contain nonextended and extended acetylcholinesterase variants along with M3 muscarinic receptors. [So] Source: FASEB J;31(2):544-555, 2017 Feb. [Is] ISSN: 1530-6860 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The observation of acetylcholinesterase (AChE) type H (AChE ), which is the predominant AChE variant in visceral organs and immune cells, in lipid rafts of muscle supports functional reasons for the raft targeting of glypiated AChE The search for these reasons revealed that liver AChE activity is mostly confined to rafts and that the liver is able to make N-extended AChE variants and target them to rafts. These results prompted us to test whether AChE and muscarinic receptors existed in the same raft. Isolation of flotillin-2-rich raft fractions by their buoyancy in sucrose gradients, followed by immunoadsorption and matrix-assisted laser desorption ionization-time of flight-mass spectrometry application, gave the following results: 1) most hepatic AChE activity emanates from AChE-H mRNA, and its product, glypiated AChE , accumulates in rafts; 2) N-extended N-AChE readthrough variant, nonglypiated N-AChE , and N-AChE tailed variant were all identified in liver rafts; and 3) M3 AChRs were observed in rafts, and coprecipitation of raft-confined N-AChE and M3 receptors by using anti-M3 antibodies showed that enzyme and receptor reside in the same raft unit. A raft domain that harbors tightly packed muscarinic receptor and AChE may represent a molecular device that, by means of which, the intensity and duration of cholinergic inputs are regulated.-Montenegro, M. F., Cabezas-Herrera, J., Campoy, F. J., Muñoz-Delgado, E., Vidal, C. J. Lipid rafts of mouse liver contain nonextended and extended acetylcholinesterase variants along with M3 muscarinic receptors. [Mh] Termos MeSH primário: Acetilcolinesterase/classificação Acetilcolinesterase/metabolismo Regulação Enzimológica da Expressão Gênica/fisiologia Variação Genética Microdomínios da Membrana/fisiologia Receptor Muscarínico M3/metabolismo [Mh] Termos MeSH secundário: Animais Encéfalo/enzimologia Fígado/enzimologia Camundongos Miocárdio/enzimologia RNA Mensageiro/genética RNA Mensageiro/metabolismo Receptor Muscarínico M3/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (RNA, Messenger); 0 (Receptor, Muscarinic M3); EC 3.1.1.7 (Acetylcholinesterase) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170901 [Lr] Data última revisão: 170901 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170203 [St] Status: MEDLINE [do] DOI: 10.1096/fj.201600609R

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[PMID]: 28122499 [Au] Autor: Kim JE; Go J; Sung JE; Lee HA; Yun WB; Hong JT; Hwang DY [Ad] Endereço: Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do, 627-706, Korea. [Ti] Título: Uridine stimulate laxative effect in the loperamide-induced constipation of SD rats through regulation of the mAChRs signaling pathway and mucin secretion. [So] Source: BMC Gastroenterol;17(1):21, 2017 Jan 26. [Is] ISSN: 1471-230X [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Uridine (Urd), which has been reported as a major component of RNA, plays an important role in various biological process including neuroprotection, biochemical modulation and glycolysis, although its role in constipation has yet to be established. Therefore, in this study, we investigated the laxative effects of Urd on chronic constipation. METHODS: The constipation phenotypes and their related mechanisms were investigated in the transverse colons of SD rats with loperamide (Lop)-induced constipation after treatment with 100 mg/kg of Urd. RESULTS: The number, weight and water contents of stools were significantly higher in the Lop + Urd treated group than the Lop + Vehicle treated group, while food intake and water consumption of the same group were maintained at a constant level. The thickness of the mucosa layer, muscle and flat luminal surface, as well as the number of goblet cells, paneth cells and lipid droplets were enhanced in the Lop + Urd treated group. Furthermore, the expression of the muscarinic acetylcholine receptors M2 and M3 (mAChR M2 and M3) at the transcriptional and translational level was recovered in the Lop + Urd treated group, while some markers such as Gα and inositol triphosphate (IP3) in their downstream signaling pathway were completely recovered by Urd treatment. Moreover, the ability for mucin secretion and the expression of membrane water channel (aquaporine 8, AQP8) were increased significantly in the Lop + Urd treated group compared with Lop + Vehicle treated group. Finally, the activity of Urd was confirmed in primary smooth muscle of rat intestine cells (pRISMC) based on Gα expression and IP3 concentration. CONCLUSIONS: The results of the present study provide the first strong evidence that Urd can be considered an important candidate for improving chronic constipation induced by Lop treatment in animal models. [Mh] Termos MeSH primário: Constipação Intestinal/tratamento farmacológico Constipação Intestinal/metabolismo Laxantes/uso terapêutico Mucinas/secreção Receptor Muscarínico M2/metabolismo Receptor Muscarínico M3/metabolismo Uridina/uso terapêutico [Mh] Termos MeSH secundário: Animais Colo Transverso/efeitos dos fármacos Colo Transverso/patologia Colo Transverso/ultraestrutura Modelos Animais de Doenças Comportamento Alimentar/efeitos dos fármacos Fosfatos de Inositol/metabolismo Intestinos/metabolismo Mucinas/efeitos dos fármacos Músculo Liso/metabolismo Ratos Sprague-Dawley Receptor Muscarínico M2/efeitos dos fármacos Receptor Muscarínico M3/efeitos dos fármacos Transdução de Sinais Uridina/metabolismo Uridina/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Inositol Phosphates); 0 (Laxatives); 0 (Mucins); 0 (Receptor, Muscarinic M2); 0 (Receptor, Muscarinic M3); 0 (inositol trispyrophosphate); WHI7HQ7H85 (Uridine) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170127 [St] Status: MEDLINE [do] DOI: 10.1186/s12876-017-0576-y

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[PMID]: 28112685 [Au] Autor: Alcacer C; Andreoli L; Sebastianutto I; Jakobsson J; Fieblinger T; Cenci MA [Ti] Título: Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson's disease therapy. [So] Source: J Clin Invest;127(2):720-734, 2017 Feb 01. [Is] ISSN: 1558-8238 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Parkinson's disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess of movement in PD has been attributed to overactivity of striatal projection neurons forming either the indirect (iSPNs) or the direct (dSPNs) pathway, respectively. Here, we investigated the two pathways' contribution to different motor features using SPN type-specific chemogenetic stimulation in rodent models of PD (PD mice) and L-DOPA-induced dyskinesia (LID mice). Using the activatory Gq-coupled human M3 muscarinic receptor (hM3Dq), we found that chemogenetic stimulation of dSPNs mimicked, while stimulation of iSPNs abolished the therapeutic action of L-DOPA in PD mice. In LID mice, hM3Dq stimulation of dSPNs exacerbated dyskinetic responses to L-DOPA, while stimulation of iSPNs inhibited these responses. In the absence of L-DOPA, only chemogenetic stimulation of dSPNs mediated through the Gs-coupled modified rat muscarinic M3 receptor (rM3Ds) induced appreciable dyskinesia in PD mice. Combining D2 receptor agonist treatment with rM3Ds-dSPN stimulation reproduced all symptoms of LID. These results demonstrate that dSPNs and iSPNs oppositely modulate both therapeutic and dyskinetic responses to dopamine replacement therapy in PD. We also show that chemogenetic stimulation of different signaling pathways in dSPNs leads to markedly different motor outcomes. Our findings have important implications for the design of effective antiparkinsonian and antidyskinetic drug therapies. [Mh] Termos MeSH primário: Levodopa/efeitos adversos Vias Neurais/metabolismo Doença de Parkinson Secundária/tratamento farmacológico Receptor Muscarínico M3/agonistas Receptores de Dopamina D2/agonistas Córtex Visual/metabolismo [Mh] Termos MeSH secundário: Animais Seres Humanos Levodopa/farmacologia Camundongos Camundongos Transgênicos Vias Neurais/patologia Neurônios/metabolismo Neurônios/patologia Doença de Parkinson Secundária/induzido quimicamente Doença de Parkinson Secundária/metabolismo Doença de Parkinson Secundária/patologia Ratos Receptor Muscarínico M3/genética Receptor Muscarínico M3/metabolismo Receptores de Dopamina D2/genética Receptores de Dopamina D2/metabolismo Córtex Visual/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Receptor, Muscarinic M3); 0 (Receptors, Dopamine D2); 46627O600J (Levodopa) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170907 [Lr] Data última revisão: 170907 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170124 [St] Status: MEDLINE

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