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Reinhard Schliebs - One of the best experts on this subject based on the ideXlab platform.
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Impairment of Cholinergic neurotransmission in adult and aged transgenic Tg2576 mouse brain expressing the Swedish mutation of human beta-amyloid precursor protein.
Brain research, 2002Co-Authors: Jenny Apelt, Ashok Kumar, Reinhard SchliebsAbstract:To address the question of whether beta-amyloid peptides also affect Cholinergic neurotransmission in vivo, brain tissue from transgenic Tg2576 mice with Alzheimer plaque pathology at ages ranging from 7 to 24 months were examined by immuno- and histochemical staining for choline acetyltransferase (ChAT) and acetycholinesterase (AChE), by assaying Cholinergic enzyme activities and high-affinity choline uptake as well muscarinic and nicotinic Cholinergic Receptor binding levels by quantitative autoradiography. Cortical and hippocampal activities of AChE and ChAT were not different between transgenic mice and non-transgenic littermates regardless of the postnatal ages examined. However, high-affinity choline uptake was reduced in the hippocampus of 21-month-old transgenic mice. In brains of 8-month-old transgenic mice which do not yet demonstrate cortical beta-amyloids, reduced binding levels of cortical and hippocampal M1-muscarinic Cholinergic Receptors were observed, which were still reduced in 17-month-old transgenic mouse brains with high plaque load as compared to non-transgenic littermates. M2-muscarinic Cholinergic Receptor binding was hardly affected in brains from 8-month-old transgenic mice, but in 17-month-old transgenic mice reduced cortical and hippocampal binding levels were observed as compared to non-transgenic controls. Decreased cortical nicotinic Cholinergic Receptor binding was detected in 17-month-old transgenic mice. The development of changes in Cholinergic synaptic markers in transgenic Tg2576 mouse brain before the onset of progressive plaque deposition provides in vivo evidence of a modulatory role of soluble beta-amyloid on Cholinergic neurotransmission and may be referred to the deficits in learning and memory also observed in these mice before significant plaque load.
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Impairment of Cholinergic neurotransmission in adult and aged transgenic Tg2576 mouse brain expressing the Swedish mutation of human β-amyloid precursor protein
Brain Research, 2002Co-Authors: Jenny Apelt, Ashok Kumar, Reinhard SchliebsAbstract:Abstract To address the question of whether β-amyloid peptides also affect Cholinergic neurotransmission in vivo, brain tissue from transgenic Tg2576 mice with Alzheimer plaque pathology at ages ranging from 7 to 24 months were examined by immuno- and histochemical staining for choline acetyltransferase (ChAT) and acetycholinesterase (AChE), by assaying Cholinergic enzyme activities and high-affinity choline uptake as well muscarinic and nicotinic Cholinergic Receptor binding levels by quantitative autoradiography. Cortical and hippocampal activities of AChE and ChAT were not different between transgenic mice and non-transgenic littermates regardless of the postnatal ages examined. However, high-affinity choline uptake was reduced in the hippocampus of 21-month-old transgenic mice. In brains of 8-month-old transgenic mice which do not yet demonstrate cortical β-amyloids, reduced binding levels of cortical and hippocampal M1-muscarinic Cholinergic Receptors were observed, which were still reduced in 17-month-old transgenic mouse brains with high plaque load as compared to non-transgenic littermates. M2-muscarinic Cholinergic Receptor binding was hardly affected in brains from 8-month-old transgenic mice, but in 17-month-old transgenic mice reduced cortical and hippocampal binding levels were observed as compared to non-transgenic controls. Decreased cortical nicotinic Cholinergic Receptor binding was detected in 17-month-old transgenic mice. The development of changes in Cholinergic synaptic markers in transgenic Tg2576 mouse brain before the onset of progressive plaque deposition provides in vivo evidence of a modulatory role of soluble β-amyloid on Cholinergic neurotransmission and may be referred to the deficits in learning and memory also observed in these mice before significant plaque load.
Paulo Caleb Júnior Lima Santos - One of the best experts on this subject based on the ideXlab platform.
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Cholinergic Receptor nicotinic alpha 5 subunit polymorphisms are associated with smoking cessation success in women
BMC Medical Genetics, 2018Co-Authors: Paulo Roberto Xavier Tomaz, Juliana Rocha Santos, Jaqueline Scholz, Tânia Ogawa Abe, Patrícia Viviane Gaya, André Brooking Negrão, José Eduardo Krieger, Alexandre Costa Pereira, Paulo Caleb Júnior Lima SantosAbstract:The identification of variants in the nicotinic acetylcholine Receptor (nAChR) subunit genes associated with smoking phenotypes are increasingly important for prevention and treatment of nicotine dependence. In the context of personalized medicine, the aims of this study were to evaluate whether Cholinergic Receptor nicotinic alpha 2 (CHRNA2), Cholinergic Receptor nicotinic alpha 3 (CHRNA3), Cholinergic Receptor nicotinic alpha 5 (CHRNA5) and Cholinergic Receptor nicotinic beta 3 (CHRNB3) polymorphisms were associated with nicotine dependence severity, and to investigate possible pharmacogenetics markers of smoking cessation treatment. This study cohort enrolled 1049 smoking patients who received pharmacological treatment (varenicline, varenicline plus bupropion, bupropion plus/or nicotine replacement therapy). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerstrom test for nicotine dependence (FTND) and Issa situational smoking scores (Issa score) were analyzed for nicotine dependence. CHRNA2 (rs2472553), CHRNA3 (rs1051730), CHRNA5 (rs16969968 and rs2036527) and CHRNB3 (rs6474413) polymorphisms were genotyped by high resolution melting analysis. Females with GA and AA genotypes for CHRNA5 rs16969968 and rs2036527 polymorphisms had higher success rate in smoking cessation treatment: 44.0% and 56.3% (rs16969968), 41.5% and 56.5% (rs2036527), respectively, compared with carriers of the GG genotypes: 35.7% (rs16969968), 34.8% (rs2036527), (P = 0.03, n = 389; P = 0.01, n = 391). The GA or AA genotypes for the rs16969968 and rs2036527 were associated with higher odds ratio for success in women (OR = 1.63; 95% CI = 1.04 to 2.54; P = 0.03 and OR = 1.59, 95% CI = 1.02 to 2.48; P = 0.04; respectively). We did not find association of these polymorphisms with nicotine dependence related scores. Polymorphisms in the CHRNA2, CHRNA3 and CHRNB3 genes were not associated with the phenotypes studied. CHRNA5 rs16969968 and rs2036527 were associated with higher success rate in the smoking cessation treatment in women. These findings might contribute to advances in personalized medicine.
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Cholinergic Receptor nicotinic alpha 5 subunit polymorphisms are associated with smoking cessation success in women
BMC, 2018Co-Authors: Paulo Roberto Xavier Tomaz, Juliana Rocha Santos, Jaqueline Scholz, Tânia Ogawa Abe, Patrícia Viviane Gaya, André Brooking Negrão, José Eduardo Krieger, Alexandre Costa Pereira, Paulo Caleb Júnior Lima SantosAbstract:Abstract Background The identification of variants in the nicotinic acetylcholine Receptor (nAChR) subunit genes associated with smoking phenotypes are increasingly important for prevention and treatment of nicotine dependence. In the context of personalized medicine, the aims of this study were to evaluate whether Cholinergic Receptor nicotinic alpha 2 (CHRNA2), Cholinergic Receptor nicotinic alpha 3 (CHRNA3), Cholinergic Receptor nicotinic alpha 5 (CHRNA5) and Cholinergic Receptor nicotinic beta 3 (CHRNB3) polymorphisms were associated with nicotine dependence severity, and to investigate possible pharmacogenetics markers of smoking cessation treatment. Methods This study cohort enrolled 1049 smoking patients who received pharmacological treatment (varenicline, varenicline plus bupropion, bupropion plus/or nicotine replacement therapy). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerström test for nicotine dependence (FTND) and Issa situational smoking scores (Issa score) were analyzed for nicotine dependence. CHRNA2 (rs2472553), CHRNA3 (rs1051730), CHRNA5 (rs16969968 and rs2036527) and CHRNB3 (rs6474413) polymorphisms were genotyped by high resolution melting analysis. Results Females with GA and AA genotypes for CHRNA5 rs16969968 and rs2036527 polymorphisms had higher success rate in smoking cessation treatment: 44.0% and 56.3% (rs16969968), 41.5% and 56.5% (rs2036527), respectively, compared with carriers of the GG genotypes: 35.7% (rs16969968), 34.8% (rs2036527), (P = 0.03, n = 389; P = 0.01, n = 391). The GA or AA genotypes for the rs16969968 and rs2036527 were associated with higher odds ratio for success in women (OR = 1.63; 95% CI = 1.04 to 2.54; P = 0.03 and OR = 1.59, 95% CI = 1.02 to 2.48; P = 0.04; respectively). We did not find association of these polymorphisms with nicotine dependence related scores. Polymorphisms in the CHRNA2, CHRNA3 and CHRNB3 genes were not associated with the phenotypes studied. Conclusion CHRNA5 rs16969968 and rs2036527 were associated with higher success rate in the smoking cessation treatment in women. These findings might contribute to advances in personalized medicine
Jenny Apelt - One of the best experts on this subject based on the ideXlab platform.
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Impairment of Cholinergic neurotransmission in adult and aged transgenic Tg2576 mouse brain expressing the Swedish mutation of human beta-amyloid precursor protein.
Brain research, 2002Co-Authors: Jenny Apelt, Ashok Kumar, Reinhard SchliebsAbstract:To address the question of whether beta-amyloid peptides also affect Cholinergic neurotransmission in vivo, brain tissue from transgenic Tg2576 mice with Alzheimer plaque pathology at ages ranging from 7 to 24 months were examined by immuno- and histochemical staining for choline acetyltransferase (ChAT) and acetycholinesterase (AChE), by assaying Cholinergic enzyme activities and high-affinity choline uptake as well muscarinic and nicotinic Cholinergic Receptor binding levels by quantitative autoradiography. Cortical and hippocampal activities of AChE and ChAT were not different between transgenic mice and non-transgenic littermates regardless of the postnatal ages examined. However, high-affinity choline uptake was reduced in the hippocampus of 21-month-old transgenic mice. In brains of 8-month-old transgenic mice which do not yet demonstrate cortical beta-amyloids, reduced binding levels of cortical and hippocampal M1-muscarinic Cholinergic Receptors were observed, which were still reduced in 17-month-old transgenic mouse brains with high plaque load as compared to non-transgenic littermates. M2-muscarinic Cholinergic Receptor binding was hardly affected in brains from 8-month-old transgenic mice, but in 17-month-old transgenic mice reduced cortical and hippocampal binding levels were observed as compared to non-transgenic controls. Decreased cortical nicotinic Cholinergic Receptor binding was detected in 17-month-old transgenic mice. The development of changes in Cholinergic synaptic markers in transgenic Tg2576 mouse brain before the onset of progressive plaque deposition provides in vivo evidence of a modulatory role of soluble beta-amyloid on Cholinergic neurotransmission and may be referred to the deficits in learning and memory also observed in these mice before significant plaque load.
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Impairment of Cholinergic neurotransmission in adult and aged transgenic Tg2576 mouse brain expressing the Swedish mutation of human β-amyloid precursor protein
Brain Research, 2002Co-Authors: Jenny Apelt, Ashok Kumar, Reinhard SchliebsAbstract:Abstract To address the question of whether β-amyloid peptides also affect Cholinergic neurotransmission in vivo, brain tissue from transgenic Tg2576 mice with Alzheimer plaque pathology at ages ranging from 7 to 24 months were examined by immuno- and histochemical staining for choline acetyltransferase (ChAT) and acetycholinesterase (AChE), by assaying Cholinergic enzyme activities and high-affinity choline uptake as well muscarinic and nicotinic Cholinergic Receptor binding levels by quantitative autoradiography. Cortical and hippocampal activities of AChE and ChAT were not different between transgenic mice and non-transgenic littermates regardless of the postnatal ages examined. However, high-affinity choline uptake was reduced in the hippocampus of 21-month-old transgenic mice. In brains of 8-month-old transgenic mice which do not yet demonstrate cortical β-amyloids, reduced binding levels of cortical and hippocampal M1-muscarinic Cholinergic Receptors were observed, which were still reduced in 17-month-old transgenic mouse brains with high plaque load as compared to non-transgenic littermates. M2-muscarinic Cholinergic Receptor binding was hardly affected in brains from 8-month-old transgenic mice, but in 17-month-old transgenic mice reduced cortical and hippocampal binding levels were observed as compared to non-transgenic controls. Decreased cortical nicotinic Cholinergic Receptor binding was detected in 17-month-old transgenic mice. The development of changes in Cholinergic synaptic markers in transgenic Tg2576 mouse brain before the onset of progressive plaque deposition provides in vivo evidence of a modulatory role of soluble β-amyloid on Cholinergic neurotransmission and may be referred to the deficits in learning and memory also observed in these mice before significant plaque load.
B Lerer - One of the best experts on this subject based on the ideXlab platform.
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why do young women smoke i direct and interactive effects of environment psychological characteristics and nicotinic Cholinergic Receptor genes
Molecular Psychiatry, 2006Co-Authors: Lior Greenbaum, Kyra Kanyas, Osnat Karni, Yifat Merbl, Tsviya Olender, Anat Horowitz, A Yakir, Doron Lancet, Edna Benasher, B LererAbstract:Why do young women smoke? I. Direct and interactive effects of environment, psychological characteristics and nicotinic Cholinergic Receptor genes
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why do young women smoke i direct and interactive effects of environment psychological characteristics and nicotinic Cholinergic Receptor genes
Molecular Psychiatry, 2006Co-Authors: Lior Greenbaum, Kyra Kanyas, Osnat Karni, Yifat Merbl, Tsviya Olender, Anat Horowitz, A Yakir, Doron Lancet, Edna Benasher, B LererAbstract:Despite the health hazards, cigarette smoking is disproportionately frequent among young women. A significant contribution of genetic factors to smoking phenotypes is well established. Efforts to identify susceptibility genes do not generally take into account possible interaction with environment, life experience and psychological characteristics. We recruited 501 female Israeli students aged 20-30 years, obtained comprehensive background data and details of cigarette smoking and administered a battery of psychological instruments. Smoking initiators (n=242) were divided into subgroups with high (n=127) and low (n=115) levels of nicotine dependence based on their scores on the Fagerstrom Tolerance Questionnaire and genotyped with noninitiators (n=142) for single nucleotide polymorphisms (SNPs) in 11 nicotinic Cholinergic Receptor genes. We found nominally significant (P<0.05) allelic and genotypic association with smoking initiation of SNP rs2072660 and multilocus haplotypes (P<0.007-0.05) in CHRNB2 and nominal (P<0.05) allelic or genotypic association of SNPs in CHRNA7 (rs1909884), CHRNA9 (rs4861065) and CHRNB3 (rs9298629) with nicotine dependence. Employing logistic regression and controlling for known risk factors, the best-fitting model for smoking initiation encompassed a 5 SNP haplotype in CHRNB2, neuroticism and novelty seeking (P=5.9 x 10(-14), Nagelkerke r(2)=0.30). For severity of nicotine dependence, two SNPs in CHRNA7 (rs1909884 and rs883473), one SNP in CHRNA5 (rs680244) and the interaction of a SNP in CHRNA7 (rs2337980) with neuroticism, were included in the model (P=2.24 x 10(-7), Nagelkerke r(2)=0.40). These findings indicate that background factors, psychological characteristics and genetic variation in nicotinic Cholinergic Receptors contribute independently or interactively to smoking initiation and to severity of nicotine dependence in young women.
Elliott M Ross - One of the best experts on this subject based on the ideXlab platform.
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regulation of phospholipase c β1 by gq and m1 muscarinic Cholinergic Receptor steady state balance of Receptor mediated activation and gtpase activating protein promoted deactivation
Journal of Biological Chemistry, 1996Co-Authors: Gloria H Biddlecome, Gabriel Berstein, Elliott M RossAbstract:Abstract The phospholipase C-β1 (PLC-β1) signaling pathway was reconstituted by addition of purified PLC to phospholipid vesicles that contained purified recombinant m1 muscarinic Cholinergic Receptor, G, and 2-4 mol % [3H]phosphatidylinositol 4,5-bisphosphate. In this system, the muscarinic agonist carbachol stimulated steady-state PLC activity up to 90-fold in the presence of GTP. Both GTP and agonist were required for PLC activation, which was observed at physiological levels of Ca (10-100 nM). PLC-β1 is also a GTPase-activating protein for G. It accelerated steady-state GTPase activity up to 60-fold in the presence of carbachol, which alone stimulated activity 6-10-fold, and increased the rate of hydrolysis of G-bound GTP by at least 100-fold. Despite this rapid hydrolysis of G-bound GTP, the Receptor maintained >10% of the total G in the active GTP-bound form by catalyzing GTP binding at a rate of at least 20-25 min, 10-fold faster than previously described. These and other kinetic data indicate that the Receptor and PLC-β1 coordinately regulate the amplitude of the PLC signal and the rates of signal initiation and termination. They also suggest a mechanism in which the Receptor, G, and PLC form a three-protein complex in the presence of agonist and GTP (stable over multiple GTPase cycles) that is responsible for PLC signaling.
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regulation of phospholipase c 1 by g and m1 muscarinic Cholinergic Receptor steady state balance of Receptor mediated activation and gtpase activating protein promoted deactivation
Journal of Biological Chemistry, 1996Co-Authors: Gloria H Biddlecome, Gabriel Berstein, Elliott M RossAbstract:Abstract The phospholipase C-β1 (PLC-β1) signaling pathway was reconstituted by addition of purified PLC to phospholipid vesicles that contained purified recombinant m1 muscarinic Cholinergic Receptor, G, and 2-4 mol % [3H]phosphatidylinositol 4,5-bisphosphate. In this system, the muscarinic agonist carbachol stimulated steady-state PLC activity up to 90-fold in the presence of GTP. Both GTP and agonist were required for PLC activation, which was observed at physiological levels of Ca (10-100 nM). PLC-β1 is also a GTPase-activating protein for G. It accelerated steady-state GTPase activity up to 60-fold in the presence of carbachol, which alone stimulated activity 6-10-fold, and increased the rate of hydrolysis of G-bound GTP by at least 100-fold. Despite this rapid hydrolysis of G-bound GTP, the Receptor maintained >10% of the total G in the active GTP-bound form by catalyzing GTP binding at a rate of at least 20-25 min, 10-fold faster than previously described. These and other kinetic data indicate that the Receptor and PLC-β1 coordinately regulate the amplitude of the PLC signal and the rates of signal initiation and termination. They also suggest a mechanism in which the Receptor, G, and PLC form a three-protein complex in the presence of agonist and GTP (stable over multiple GTPase cycles) that is responsible for PLC signaling.
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regulation of phospholipase c β1 by gq and m1 muscarinic Cholinergic Receptor steady state balance of Receptor mediated activation and gtpase activating protein promoted deactivation
Journal of Biological Chemistry, 1996Co-Authors: Gloria H Biddlecome, Gabriel Berstein, Elliott M RossAbstract:The phospholipase C-beta1 (PLC-beta1) signaling pathway was reconstituted by addition of purified PLC to phospholipid vesicles that contained purified recombinant m1 muscarinic Cholinergic Receptor, Gq, and 2-4 mol % [3H]phosphatidylinositol 4,5-bisphosphate. In this system, the muscarinic agonist carbachol stimulated steady-state PLC activity up to 90-fold in the presence of GTP. Both GTP and agonist were required for PLC activation, which was observed at physiological levels of Ca2+ (10-100 nM). PLC-beta1 is also a GTPase-activating protein for Gq. It accelerated steady-state GTPase activity up to 60-fold in the presence of carbachol, which alone stimulated activity 6-10-fold, and increased the rate of hydrolysis of Gq-bound GTP by at least 100-fold. Despite this rapid hydrolysis of Gq-bound GTP, the Receptor maintained >10% of the total Gq in the active GTP-bound form by catalyzing GTP binding at a rate of at least 20-25 min-1, approximately 10-fold faster than previously described. These and other kinetic data indicate that the Receptor and PLC-beta1 coordinately regulate the amplitude of the PLC signal and the rates of signal initiation and termination. They also suggest a mechanism in which the Receptor, Gq, and PLC form a three-protein complex in the presence of agonist and GTP (stable over multiple GTPase cycles) that is responsible for PLC signaling.