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Lack of effect of McN-A-343 on membrane current and contraction in guinea pig ventricular myocytes

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期290卷 641-648页

作者： Shen, JB Jiang, B Pappano, AJ Univ Connecticut Ctr Hlth Dept Pharmacol Farmington CT 06030 USA

We asked whether agonist occupancy of M-1 muscarinic receptor (mAChR) causes increased L-type Ca2+ [I-Ca(L)] and contractions in ventricular myocytes. Voltage-clamp pulses evoked I-Ca(L) in guinea pig ventricular myocytes superfused with Ty rode's solution (22-24 degrees C). The mAChR agonists carbachol (Cch, nonselective), McN-A-343 (McN, M-1-selective), and oxo otremorine (Oxo, M-2-selective) were tested at 0.1 mM. None of these agonists affected basal I-Ca(L). McN did not change isoproterenol-stimulated I-Ca(L) in 13 of 15 cells. The slight decrease in two cells was not muscarinic because atropine (1 mu M) did not antagonize it. Carbachol or Oxo decreased isoproterenol-stimulated I-Ca(L) by 87 +/- 6.7 (n = 8 cells) and 49 +/- 9.0% (n = 4 cells), respectively. Atropine blocked inhibition by Cch or Oxo. External stimulation evoked contractions of single myocytes (35 degrees C). McN increased contraction in 1 of 22 cells stimulated at 0.2 Hz and in 0 of 16 cells stimulated at 1.0 Hz. Carbachol significantly increased contraction in 10 of 15 cells at 0.2 Hz and in 8 of 10 cells at 1.0 Hz stimulus frequency. Summarily, the M-1-selective agonist McN had a negligible role to regulate I-Ca(L). The antiadrenergic effect of mAChR agonists is attributable to M-2 receptor occupancy. That Cch, but not McN, increased cell shortening excludes participation of M-1 mAChR in the stimulant effect of Cch on guinea pig ventricular myocyte contractions.

关键词：肾上腺素能β激动剂/药理学钙通道/代谢钙通道 L型卡巴胆碱/药理学细胞膜/药物作用细胞膜/代谢环AMP/代谢电生理学心脏/药物作用心室/细胞学心室/药物作用异丙肾上腺素/药理学毒蕈碱激动剂/药理学心肌收缩/药物作用氧代震颤素/药理学膜片钳术受体毒蕈碱M1 受体毒蕈碱M2 受体毒蕈碱/药物作用受体毒蕈碱/代谢动物豚鼠

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6β-acyloxy(nor)tropanes:: Affinities for antagonist/agonist binding sites on transfected and native muscarinic receptors

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JOURNAL OF MEDICINAL CHEMISTRY 2000年第13期43卷 2514-2522页

作者： Daly, JW Gupta, TH Padgett, WL Pei, XF NIDDK Bioorgan Chem Lab NIH Bethesda MD 20892 USA

A series of esters of 6 beta-hydroxynortropane and the N-methyl analogue 6 beta-tropanol were synthesized and screened versus binding of an antagonist (quinuclidinyl benzilate) and an agonist (oxotremorine-M) at sites on human m(1)-, m(2)-, m(3)-, and m(4)-muscarinic receptors in transfected cell membranes and on native M-1-muscarinic receptors in rat brain membranes and native M-2-muscarinic receptors in rat heart membranes. Most 6 beta-acyloxy(nor)tropanes had higher affinity versus oxotremorine-M binding compared to quinuclidinyl benzilate binding at transfected m(1)- and native M-1-receptors, indicative of agonist activity. 6 beta-Acetoxynortropane had K-i values versus oxotremorine-M binding at m(1)-, m(2)-, and m(4)-receptors ranging from 4 to 7 nM. N-Methylation reduced affinity greatly as did increasing the size of the acyl moiety. The affinity of 6 beta-benzoyloxynortropane and other analogues with larger acyl moieties was little affected by N-methylation or in some cases was increased. 6 beta-Acyloxy(nor)tropanes and classical muscarinic agonists, such as muscarine and oxotremorine, had higher affinity versus oxotremorine-M binding compared to quinuclidinyl benzilate binding at native M-2-muscarinic receptors of heart, but not at transfected m(2)-muscarinic receptors. Antagonist/agonist binding ratios were not obtained for transfected m(3)-receptors, since significant oxotremorine-M binding could not be detected. 6 beta-Acyloxy(nor)tropane, two other (nor)tropanes, and the classical muscarinic agonists had higher affinity versus agonist binding compared to antagonist binding for transfected m(4)-receptors. The antagonist/agonist binding ratio method is clearly not always reliable for predicting agonist activity at muscarinic receptors.

关键词：结合部位 CHO细胞大脑皮质/代谢仓鼠亚科毒蕈碱激动剂/化学合成毒蕈碱激动剂/化学毒蕈碱激动剂/代谢毒蕈碱激动剂/药理学心肌/代谢氧代震颤素/类似物和衍生物氧代震颤素/代谢奎宁环苯齐酸盐/代谢受体毒蕈碱M1 受体毒蕈碱M2 受体毒蕈碱M3 受体毒蕈碱M4 受体毒蕈碱/药物作用受体毒蕈碱/代谢转染托烷类/化学合成托烷类/化学托烷类/代谢托烷类/药理学动物人类大鼠

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Structural elements near the C-terminus are responsible for changes in nicotinic receptor gating kinetics following patch excision

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第3期527卷 405-417页

作者： Akk, G Steinbach, JH Washington Univ Sch Med Dept Anesthesiol St Louis MO 63110 USA

1. We have studied the effect of patch excision on the gating kinetics of muscle nicotinic acetylcholine receptors transiently expressed in HEK 293 cells. The experiments were performed on embryonic and adult wild-type, and several mutated, receptors using acetylcholine, carbamylcholine and tetramethylammonium as agonists. 2. We show that patch excision of cell-attached patches into the inside-out configuration led to a reduction of mean open duration in receptors containing a gamma-subunit (embryonic) but not an epsilon-subunit (adult receptors). 3. Kinetic analysis of an embryonic receptor containing a mutated residue, alpha Y93F, showed that the reduction in the mean open duration upon patch excision was mainly caused by an increase in the channel closing rate constant. This was confirmed by experiments on embryonic wild-type receptors using carbamylcholine as an agonist with low efficacy. 4. By expressing receptors containing chimeric gamma-epsilon subunits we found that segments of the gamma-subunit corresponding to a region within the M3-M4 linker (the amphipathic helix, HA) and the M4 transmembrane domain were required for the reduction in channel open duration after excision. 5. The results indicate hat particular residues in both M4 and HA are required to allow the change in open time after excision. This finding suggests that there is an interaction between these two regions in determining the modulation of gating kinetics.

关键词：乙酰胆碱/药理学算法氨基酸序列卡巴胆碱/药理学细胞系 DNA/生物合成 DNA/遗传学电生理学神经节兴奋药/药理学离子通道闸门/药物作用离子通道闸门/生理学动力学分子序列数据毒蕈碱激动剂/药理学肌骨骼/细胞学膜片钳术季胺类化合物/药理学受体烟碱/药物作用动物小鼠

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Effects of elevated cytoplasmic calcium and protein kinase C on endoplasmic reticulum structure and function in HEK293 cells

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CELL CALCIUM 2000年第3期27卷 175-185页

作者： Ribeiro, CMP McKay, RR Hosoki, E Bird, GS Putney, JW NIEHS NIH Res Triangle Pk NC 27709 USA

In human embryonic kidney (HEK) cells stably transfected with green fluorescent protein targeted to the endoplasmic reticulum (ER), elevation of intracellular Ca2+ ([Ca2+](i)) altered ER morphology, making it appear punctate. Electron microscopy revealed that these punctate structures represented circular and branched rearrangements of the endoplasmic reticulum, but did not involve obvious swelling or pathological fragmentation. Activation of protein kinase C with phorbol 12-myristate 13-acetate (PMA), prevented the effects of ionomycin on ER structure without affecting the elevation of [Ca2+](i). These results suggest that protein kinase C activation alters cytoplasmic or ER components underlying the effects of high [Ca2+](i) on ER structure. Treatment of HEK cells with PMA also reduced the size of the thapsigargin-sensitive Ca2+ pool and inhibited Ca2+ entry in response to thapsigargin. Thus, protein kinase C activation has multiple actions on the calcium storage and signalling function of the endoplasmic reticulum in HEK cells: (1) reduced intracellular Ca2+ storage capacity, (2) inhibition of capacitative Ca2+ entry, and (3) protection of the endoplasmic reticulum against the effects of high [Ca2+](i). (C) 2000 Harcourt Publishers Ltd.

关键词：钙/代谢钙信号细胞系细胞光度测定法内质网/药物作用内质网/代谢内质网/超微结构酶抑制剂/药理学荧光染料 Fura-2/代谢离子霉素/药理学离子载体/药理学肾氯醋甲胆碱/药理学显微镜检查共焦显微镜检查电子毒蕈碱激动剂/药理学蛋白激酶C/代谢重组融合蛋白质类/遗传学重组融合蛋白质类/代谢十四酰佛波乙酯/药理学毒胡萝卜内酯/药理学转染人类

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Obstructive response of human bladder to BPH vs. rabbit bladder response to partial outlet obstruction: A direct comparison

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NEUROUROLOGY AND URODYNAMICS 2000年第5期19卷 609-629页

作者： Levin, RM Haugaard, N O'Connor, L Buttyan, R Das, A Dixon, JS Gosling, JN Coll Pharm Div Basic & Pharmaceut Sci Albany NY 12208 USA Stratton Vet Affairs Med Ctr Albany NY USA Univ Penn Sch Med Div Urol Philadelphia PA 19104 USA Columbia Univ Sch Med Dept Urol New York NY USA Albany Med Coll Albany NY 12208 USA Stanford Univ Sch Med Div Anat Stanford CA 94305 USA

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Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjogren's syndrome

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ARTHRITIS AND RHEUMATISM 2000年第7期43卷 1647-1654页

作者： Waterman, SA Gordon, TP Rischmueller, M Univ Adelaide Dept Physiol Adelaide SA 5005 Australia Flinders Univ S Australia Adelaide SA 5001 Australia Queen Elizabeth Hosp Adelaide SA Australia

Objective. Sjogren's syndrome (SS) is an autoimmune disorder characterized by dry eyes and mouth (sicca syndrome) and lymphocytic infiltration of the lacrimal and salivary glands. Abnormalities of parasympathetic neurotransmission may contribute to the glandular dysfunction, In this study, we used a functional assay to investigate autoantibody-mediated effects on parasympathetic neurotransmission and smooth muscle contraction. Methods. Serum and purified IgG were obtained from patients with primary and secondary SS and from control subjects. Contraction of isolated bladder strips in response to stimulation of M-3-muscarinic receptors by a muscarinic receptor agonist, carbachol, or by endogenous acetylcholine released from postganglionic parasympathetic nerves was measured before and after the addition of patient serum or IgG, Results. Sera from 5 of 9 patients with primary SS and from 6 of 6 patients with secondary SS inhibited carbachol-evoked bladder contraction by similar to 50%, Sera from these patients also inhibited the action of neuronally released acetylcholine at M-3-muscarinic receptors, Sera from 7 of 8 healthy individuals, from patients with rheumatoid arthritis without sicca symptoms, and from patients with systemic lupus erythematosus had no effect. The anti-muscarinic receptor activity was localized in the IgG fraction, since purified IgG from patients with SS also inhibited agonist- and nerve-evoked contractions. In this preliminary study, the autoantibodies seemed to be associated with the presence of bladder symptoms and other autonomic features. Conclusion. Autoantibodies that act as antagonists at M-3-muscarinic receptors on smooth muscle occur in a subset of patients with primary and secondary SS, Their presence in secondary SS was unexpected and provides new evidence for a common pathogenetic link between primary and secondary SS, These autoantibodies appear to contribute to sicca symptoms and may explain associated features of autonomic dysfun

关键词：乙酰胆碱/代谢自身抗体/血液自身抗体/药理学卡巴胆碱/药理学免疫球蛋白G/药理学红斑狼疮系统性/血液红斑狼疮系统性/免疫学毒蕈碱激动剂/药理学肌收缩/药物作用肌平滑/药物作用副交感神经系统/药物作用副交感神经系统/免疫学副交感神经系统/代谢受体毒蕈碱M3 受体毒蕈碱/免疫学干燥综合征/血液干燥综合征/免疫学突触传递/药物作用突触传递/免疫学膀胱/药物作用成年人老年人老年人 80以上动物女(雌)性人类男(雄)性小鼠中年人

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Pharmacological characterization of endogenous acetylcholine release from primary septal cultures

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期292卷 692-697页

作者： Auld, DS Day, JC Mennicken, FO Quirion, E Douglas Hosp Res Ctr Verdun PQ H4H 1R3 Canada McGill Univ Fac Med Dept Neurol & Neurosurg Montreal PQ Canada McGill Univ Fac Med Dept Pharmacol & Therapeut Montreal PQ Canada McGill Univ Fac Med Dept Psychiat Montreal PQ Canada

A detailed investigation of endogenous acetylcholine (ACh) release from primary embryonic septal cultures is described in this study. Applications of veratridine (25 mu M) or increasing extracellular concentrations of K+ (6-100 mM) induced robust increases of endogenous ACh release (similar to 500-15,000 fmol/well/10 min). Release stimulated with K+ (25 mM) was sustainable and did not differ significantly over 180 min. ACh release was dependent on extracellular choline and decreased proportionally to choline concentrations (0-10 mu M). For example, after 30 min of stimulation with K+ (25 mM), release in the absence of extracellular choline was similar to 25% of that associated with 10 mM choline. The vesicular transport blocker vesamicol (0-5 mu M) almost completely prevented stimulated and basal ACh release at the highest concentration evaluated, which suggests a mostly vesicular mode of release in this model. The M-2-like muscarinic receptor antagonist AF-DX 384 (0-10 mu M) enhanced stimulated ACh release (similar to 150% at the highest concentration evaluated), whereas the nonspecific muscarinic receptor agonist oxotremorine (0-10 mu M) decreased stimulated release (similar to 60% at the highest concentration evaluated), suggesting that functional muscarinic autoreceptors exist in primary embryonic septal cultures. Novel findings concerning ACh release from primary embryonic septal cultures are reported herein, and the demonstration of ACh release gives further credit to the use of these cultures for studying cholinergic system functioning and in relation to physiology and pathology.

关键词：乙酰胆碱/分泌细胞培养的胆碱/生理学胆碱O-乙酰转移酶/代谢色谱法高压液相剂量效应关系药物药物相互作用胚胎哺乳动物/代谢毒蕈碱激动剂/药理学神经肌肉去极化药/药理学氧代震颤素/药理学抗副交感神经药/药理学哌啶类/药理学哌仑西平/类似物和衍生物哌仑西平/药理学钾/药理学脑中隔/代谢时间因素藜芦定/药理学动物大鼠

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[4-[[N-(3-Chlorophenyl)carbamoyl]oxy]-2-butynyl]-trimethylammonium (McN-A-343)-related compounds.: Effect of the butynyl chain inclusion into an aromatic unit on the potency for muscarinic receptors

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BIOORGANIC & MEDICINAL CHEMISTRY 2000年第4期8卷 681-689页

作者： Tumiatti, V Angeli, P Andrisano, V Bolognesi, ML Cavalli, A Marucci, G Minarini, A Recanatini, M Rosini, M Melchiorre, C Univ Bologna Dept Pharmaceut Sci I-40126 Bologna Italy Univ Camerino Dept Chem Sci I-62032 Camerino MC Italy

A series of derivatives of the known M-1 selective muscarinic receptor agonist McN-A-343 (1) was designed with the aim of investigating the effects of structural variations on both the butynyl chain and the phenyl ring of 1. The butynyl chain was replaced with an aromatic spacer, and the effects of such a modification on the stereoelectronic properties of the molecules were theoretically studied and considered compatible with muscarinic receptor affinity. Substituents on the phenyl ring of 1 were selected so as to vary their electronic and hydrophobic properties. This design strategy did not produce muscarinic M-1 receptor agonists more potent than the prototype 1, even if some analogues displayed functional selectivity for different muscarinic receptor subtypes. Compounds 3 and 7 were selective agonists towards muscarinic M-3 receptors, while compounds 14, 16 and 18 were selective muscarinic M-2 receptor agonists. The most interesting derivative was 8, a full agonist at muscarinic M-3 receptors devoid of activity at both muscarinic M-1 and M-2 subtypes. The pharmacological profile of the series was further characterized by studying the anticholinesterase and miotic activities of some representative compounds. Compounds 3-8 turned out to be weak acetylcholinesterase inhibitors, while derivatives 4, 6, 8 and ii were able to significantly reduce the pupillary diameter in rabbit, indicating 8 as an effective miotic agent, (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词： (4-(m-氯苯基氨甲酰氧)-2-丁炔基)三甲基溴化铵氯化物/化学 (4-(m-氯苯基氨甲酰氧)-2-丁炔基)三甲基溴化铵氯化物/药理学瞳孔缩小模型分子毒蕈碱激动剂/化学毒蕈碱激动剂/药理学肌收缩/药物作用构效关系动物豚鼠男(雄)性兔

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Protein kinase C mediates muscarinic block of intrinsic bursting in rat hippocampal neurons

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JOURNAL OF PHYSIOLOGY-LONDON 1999年第1期518卷 71-79页

作者： Alroy, G Su, HL Yaari, Y Hebrew Univ Jerusalem Hadassah Fac Med Inst Med Sci Dept Physiol IL-91120 Jerusalem Israel

1. Acetylcholine released from basal forebrain cholinergic fibres suppresses intrinsic bursting in cortical pyramidal cells through activation of muscarinic receptors. The signal transduction pathway mediating this action is not known. We used intracellular recordings from CA1 pyramidal cells in hippocampal slices to investigate the involvement of protein kinase C (PKC) in this cholinergic function. 2. Bath-applied carbachol (CCh;5 mu M) consistently suppressed intrinsic bursting in an atropine-sensitive (1 mu M) manner. 3. Intrinsic bursting was suppressed by 4 beta-phorbol 12,13-dibutyrate (PDBu;5-10 mu M), a potent PKC activator, but not by the inactive phorbol ester 4 alpha-phorbol 12,13-didecanoate (PDC;50 mu M). Prior application of the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7;10 mu M) extracellularly or intracellularly prevented the PDBu effect. 4. Pretreatment with H7, but not with the broad-spectrum kinase inhibitor N-(2-guanidino-ethyl)-5-isoquinoline-sulfonyl hydrochloride (HA1004;10 mu M), prevented the CCh-induced suppression of bursting. 5. The active component of the spike after-depolarization (ADP) was reduced by CCh in an atropine-sensitive manner. This effect was mimicked by PDBu, but not by PDC. It was prevented by pretreatment with H7, but not with HA1004. 6. Blocking most K+ currents with Ca2+-free , TEA-containing saline induced large TTX-sensitive plateau potentials lasting > 150 ms, driven by a persistent Na+ current. These potentials were suppressed by PDBu, but not by PDC. Pretreatment with H7 prevented the PDBu-induced suppression of the plateau potentials. 7. We conclude that cholinergic suppression of intrinsic bursting in hippocampal CA1 pyramidal cells is mediated by muscarinic activation of PKC, which down-regulates the persistent Na+ current underlying slow depolarizing potentials in these neurons.

关键词： 1-(5-异喹啉磺酰基)-2-甲基哌嗪/药理学乙酰胆碱/生理学阿托品/药理学卡巴胆碱/药理学酶抑制剂/药理学海马/细胞学海马/药物作用海马/生理学毒蕈碱激动剂/药理学毒蕈碱拮抗剂/药理学膜片钳术佛波醇12 13-二丁酸盐/药理学蛋白激酶C/生理学锥体细胞/药物作用锥体细胞/生理学受体毒蕈碱/药物作用受体毒蕈碱/生理学信号传导/生理学四乙基铵/药理学河豚毒素/药理学动物大鼠

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Depolarization affects the binding properties of muscarinic acetylcholine receptors and their interaction with proteins of the exocytic apparatus

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第41期274卷 29519-29528页

作者： Ilouz, N Branski, L Parnis, J Parnas, H Linial, M Hebrew Univ Jerusalem Alexander Silberman Inst Life Sci Dept Biol Chem IL-91904 Jerusalem Israel Hebrew Univ Jerusalem Alexander Silberman Inst Life Sci Otto Loewi Ctr Mol & Cellular Neurobiol IL-91904 Jerusalem Israel

Membrane depolarization is the signal that triggers release of neurotransmitter from nerve terminals. As a result of depolarization, voltage-dependent Ca2+ channels open, level of intracellular Ca2+ increases. and release of neurotransmitter commences. Previous study had shown that in rat brain synaptosomes, muscarinic acetylcholine (ACh) receptors (mAChRs) interact with soluble NSF attachment protein receptor proteins of the exocytic machinery in a voltage-dependent manner. It was suggested that this interaction might control the rapid, synchronous release of acetylcholine, The present study investigates the mechanism for such a voltage-dependent interaction. Here we show that depolarization shifts mAChRs, specifically the m2 receptor subtype, to a low affinity state toward its agonists, At resting potential, mAChRs are in a high affinity state (K-d of similar to 20 nM) and they shift to a low affinity state (K-d of tens of mu M) upon membrane depolarization. In addition, interaction between m2 receptor subtype and the exocytic machinery increases with receptor occupancy. Both phenomena are independent of Ca2+ influx. We propose that these results may explain control of ACh release from nerve terminals. At resting potential the exocytic machinery is clamped due to its interaction with the occupied mAChR and depolarization relieves this interaction. This, together with Ca2+ influx, enables release of ACh to commence.

关键词：乙酰胆碱/代谢结合竞争性脑/代谢 CHO细胞钙/代谢卡巴胆碱/代谢仓鼠亚科胞吐作用膜电位膜蛋白质类/代谢毒蕈碱激动剂/药理学毒蕈碱拮抗剂/药理学 N-甲基东莨菪碱/代谢蛋白质结合 Qa-SNARE蛋白质类受体毒蕈碱/分类受体毒蕈碱/代谢突触体/代谢转染动物人类大鼠

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