The Experts below are selected from a list of 87999 Experts worldwide ranked by ideXlab platform
Robert J. Walker - One of the best experts on this subject based on the ideXlab platform.
-
The actions of muscle relaxants at nicotinic Acetylcholine Receptor isoforms
European Journal of Pharmacology, 1998Co-Authors: Catherine M. Garland, Richard C. Foreman, John E. Chad, Lindy Holden-dye, Robert J. WalkerAbstract:The pharmacological diversity of the different isoforms of the nicotinic Acetylcholine Receptor arises from the diversity of the subunits that assemble to form the native Receptors. The aim of this study was to investigate the actions of the muscle relaxants d-tubocurarine, pancuronium and vecuronium on different isoforms of nicotinic Acetylcholine Receptors (mouse foetal muscle, mouse adult muscle and a rat neuronal), using the Xenopus oocyte expression system. Oocytes were injected with cRNAs for ?, ?, ?, ? subunits (the native foetal muscle subunit combination), or with cRNAs for ?, ?, , ? subunits (the native adult muscle subunit combination), or with cRNAs for ?4?2 subunits (a putative native neuronal subunit combination). Acetylcholine had a similar potency at all three subunit combinations (EC50 11.6, 17.4 and 19.1 ?M, respectively). At all three Receptor types, d-tubocurarine and pancuronium blocked the responses elicited by Acetylcholine in a reversible manner. Furthermore, the inhibition of the Acetylcholine currents for the foetal and adult nicotinic Acetylcholine Receptor by pancuronium and d-tubocurarine was independent of the holding voltage over the range ?100 to ?40 mV. In oocytes expressing the foetal muscle nicotinic Acetylcholine Receptors the inhibition of the current in response to 100 ?M Acetylcholine by 10 nM d-tubocurarine was 29±5% (mean±S.E.M.; n=7), and the inhibition by 10 nM pancuronium was 39±6% (mean±S.E.M.; n=8; P>0.05 vs. d-tubocurarine). However, in the adult form of the muscle nicotinic Acetylcholine Receptor, 10 nM d-tubocurarine and 10 nM pancuronium were both more effective at blocking the response to 100 ?M Acetylcholine compared to the foetal muscle nicotinic Acetylcholine Receptor, with values of 55±5% (P
-
The actions of muscle relaxants at nicotinic Acetylcholine Receptor isoforms
European journal of pharmacology, 1998Co-Authors: Catherine M. Garland, Richard C. Foreman, John E. Chad, Lindy Holden-dye, Robert J. WalkerAbstract:The pharmacological diversity of the different isoforms of the nicotinic Acetylcholine Receptor arises from the diversity of the subunits that assemble to form the native Receptors. The aim of this study was to investigate the actions of the muscle relaxants d-tubocurarine, pancuronium and vecuronium on different isoforms of nicotinic Acetylcholine Receptors (mouse foetal muscle, mouse adult muscle and a rat neuronal), using the Xenopus oocyte expression system. Oocytes were injected with cRNAs for alpha, beta, gamma, delta subunits (the native foetal muscle subunit combination), or with cRNAs for alpha, beta, epsilon, delta subunits (the native adult muscle subunit combination), or with cRNAs for alpha4beta2 subunits (a putative native neuronal subunit combination). Acetylcholine had a similar potency at all three subunit combinations (EC50 11.6, 17.4 and 19.1 microM, respectively). At all three Receptor types, d-tubocurarine and pancuronium blocked the responses elicited by Acetylcholine in a reversible manner. Furthermore, the inhibition of the Acetylcholine currents for the foetal and adult nicotinic Acetylcholine Receptor by pancuronium and d-tubocurarine was independent of the holding voltage over the range -100 to -40 mV. In oocytes expressing the foetal muscle nicotinic Acetylcholine Receptors the inhibition of the current in response to 100 microM Acetylcholine by 10 nM d-tubocurarine was 29 +/- 5% (mean +/- S.E.M.; n = 7), and the inhibition by 10 nM pancuronium was 39 +/- 6% (mean +/- S.E.M.; n = 8; P > 0.05 vs. d-tubocurarine). However, in the adult form of the muscle nicotinic Acetylcholine Receptor, 10 nM d-tubocurarine and 10 nM pancuronium were both more effective at blocking the response to 100 microM Acetylcholine compared to the foetal muscle nicotinic Acetylcholine Receptor, with values of 55 +/- 5% (P < 0.01; n = 12) and 60 +/- 4% (P < 0.001; n = 10), respectively. Thus the developmental switch from the gamma to the epsilon subunit alters the antagonism of the nicotinic Acetylcholine Receptor for both pancuronium and d-tubocurarine. Vecuronium was more potent than pancuronium. One nM vecuronium reduced the response to 100 microM Acetylcholine by 71 +- 6% (n = 10) for foetal and 63 +/- 5% (n = 4) for adult nicotinic Acetylcholine Receptors. In the alpha4beta2 neuronal nicotinic Acetylcholine Receptor combination, 10 nM pancuronium was a more effective antagonist of the response to 100 microM Acetylcholine (69 +/- 6%, n = 6) than 10 nM d-tubocurarine (30 +/- 5%; n = 6; P < 0.05 compared to pancuronium). This is in contrast to the adult muscle nicotinic Acetylcholine Receptor, where pancuronium and d-tubocurarine were equieffective. The expression of the beta2 subunit with muscle alpha, epsilon and delta subunits formed a functional Receptor which was blocked by pancuronium and d-tubocurarine in a similar manner to the alphabeta1epsilondelta subunit consistent with the hypothesis that the beta subunit is not a major determinant in the action of this drug at the adult muscle nicotinic Acetylcholine Receptor.
Hyun-dong Paik - One of the best experts on this subject based on the ideXlab platform.
-
Effects of quercetin on α9α10 nicotinic Acetylcholine Receptor-mediated ion currents
European Journal of Pharmacology, 2010Co-Authors: Sunhye Choi, Taejoon Shin, Sunghee Hwang, Hyun-dong PaikAbstract:Abstract Quercetin, one of the flavonoids, is a low molecular weight substance found in fruits and vegetables. Quercetin, like other flavonoids, has a wide range of neuropharmacological actions and antioxidant effects. The α9α10 nicotinic Acetylcholine Receptor is one of the numerous nicotinic Acetylcholine Receptors that exist as a heteropentameric form between efferent olivocochlear fibers and hair cells of the cochlea. In this study, we report the effects of quercetin on rat α9α10 nicotinic Acetylcholine Receptor-mediated ion currents using the two-electrode voltage-clamp technique. Treatment with Acetylcholine evoked inward currents (IACh) in oocytes heterologously expressing the α9α10 nicotinic Acetylcholine Receptor. Quercetin blocked IACh in concentration-dependent and reversible manners, and the blocking effect on IACh was stronger with pre-application than co-application of quercetin. The half maximal inhibitory concentration (IC50) of quercetin was 45.4 ± 10.1 μM. Quercetin-mediated IACh inhibition was not affected by Acetylcholine concentration and was independent of membrane-holding potential. Although the inhibitory effect of quercetin was significantly attenuated in the absence of extracellular Ca2+, the action of quercetin was independent of extracellular Ca2+ concentration, indicating that the presence of extracellular Ca2+ might be needed for quercetin-related effects and might play an important role in quercetin-mediated regulation of the α9α10 nicotinic Acetylcholine Receptor. These results indicate that quercetin-mediated regulation of the α9α10 nicotinic Acetylcholine Receptor could provide a molecular basis for quercetin actions at the cellular level.
Michelle Vincler - One of the best experts on this subject based on the ideXlab platform.
-
Peripheral nerve injury alters spinal nicotinic Acetylcholine Receptor pharmacology
European Journal of Pharmacology, 2008Co-Authors: Tracey Young, Shannon Wittenauer, Renee Parker, Michelle VinclerAbstract:Abstract Nicotinic Acetylcholine Receptors are widely expressed in the rat spinal cord and modulate innocuous and nociceptive transmission. The present studies were designed to investigate the plasticity of spinal nicotinic Acetylcholine Receptors modulating mechanosensitive information following spinal nerve ligation. A tonic inhibitory cholinergic tone mediated by dihydro-β-erythroidine- (DHβE) and methyllycaconitine- (MLA) sensitive nicotinic Acetylcholine Receptors was identified in the normal rat spinal cord and cholinergic tone at both populations of nicotinic Acetylcholine Receptors was lost ipsilateral to spinal nerve ligation. The administration of intrathecal nicotinic Acetylcholine Receptor agonists reduced mechanical paw pressure thresholds with a potency of epibatidine = A-85380 >> nicotine > choline in the normal rat. Following spinal nerve ligation, intrathecal epibatidine and nicotine produced an ipsilateral antinociception, but intrathecal A-85380 and choline did not. The antinociceptive response to intrathecal nicotine was blocked with the α7⁎ and α9α10⁎-selective nicotinic Acetylcholine Receptor antagonist, MLA, and the αβ heteromeric nicotinic Acetylcholine Receptor antagonist, DHβE. The antinociceptive effects of both intrathecal nicotine and epibatidine were mediated by GABAA Receptors. Spinal [3H]epibatidine saturation binding was unchanged in spinal nerve-ligated rats, but spinal nerve ligation did increase the ability of nicotine to displace [3H]epibatidine from spinal cord membranes. Spinal nerve ligation altered the expression of nicotinic Acetylcholine Receptor subunits ipsilaterally, with a large increase in the modulatory α5 subunit. Taken together these results suggest that pro- and antinociceptive populations of spinal nicotinic Acetylcholine Receptors modulate the transmission of mechanosensitive information and that spinal nerve ligation-induced changes in spinal nicotinic Acetylcholine Receptors likely result from a change in subunit composition rather than overt loss of nicotinic Acetylcholine Receptor subtypes.
-
Peripheral nerve injury alters spinal nicotinic Acetylcholine Receptor pharmacology.
European journal of pharmacology, 2008Co-Authors: Tracey Young, Shannon Wittenauer, Renee Parker, Michelle VinclerAbstract:Nicotinic Acetylcholine Receptors are widely expressed in the rat spinal cord and modulate innocuous and nociceptive transmission. The present studies were designed to investigate the plasticity of spinal nicotinic Acetylcholine Receptors modulating mechanosensitive information following spinal nerve ligation. A tonic inhibitory cholinergic tone mediated by dihydro-beta-erythroidine- (DHbetaE) and methyllycaconitine- (MLA) sensitive nicotinic Acetylcholine Receptors was identified in the normal rat spinal cord and cholinergic tone at both populations of nicotinic Acetylcholine Receptors was lost ipsilateral to spinal nerve ligation. The administration of intrathecal nicotinic Acetylcholine Receptor agonists reduced mechanical paw pressure thresholds with a potency of epibatidine=A-85380>>nicotine>choline in the normal rat. Following spinal nerve ligation, intrathecal epibatidine and nicotine produced an ipsilateral antinociception, but intrathecal A-85380 and choline did not. The antinociceptive response to intrathecal nicotine was blocked with the alpha7 and alpha9alpha10-selective nicotinic Acetylcholine Receptor antagonist, MLA, and the alphabeta heteromeric nicotinic Acetylcholine Receptor antagonist, DHbetaE. The antinociceptive effects of both intrathecal nicotine and epibatidine were mediated by GABA(A) Receptors. Spinal [(3)H]epibatidine saturation binding was unchanged in spinal nerve-ligated rats, but spinal nerve ligation did increase the ability of nicotine to displace [(3)H]epibatidine from spinal cord membranes. Spinal nerve ligation altered the expression of nicotinic Acetylcholine Receptor subunits ipsilaterally, with a large increase in the modulatory alpha5 subunit. Taken together these results suggest that pro- and antinociceptive populations of spinal nicotinic Acetylcholine Receptors modulate the transmission of mechanosensitive information and that spinal nerve ligation-induced changes in spinal nicotinic Acetylcholine Receptors likely result from a change in subunit composition rather than overt loss of nicotinic Acetylcholine Receptor subtypes.
Howard H Wang - One of the best experts on this subject based on the ideXlab platform.
-
Molecular environment of the phencyclidine binding site in the nicotinic Acetylcholine Receptor membrane
The Journal of Membrane Biology, 1991Co-Authors: Andrew L. Palma, Howard H WangAbstract:Phencyclidine is a highly specific noncompetitive inhibitor of the nicotinic Acetylcholine Receptor. In a novel approach to study this site, a spin-labeled analogue of phencyclindine. 4-phenyl-4-(1-piperidinyl)-2.2.6.6.-tetramethylpiperidinoxyl (PPT) was synthesized. The binding of PPT inhibits^86Rb flux (IC_50=6.6μ m ), and [^3H] phencyclidine binding to both resting and desensitized Acetylcholine Receptor (IC_50=17 μ m and 0.22 μ m , respectively). From an indirect Hill plot of the inhibition of [^3H]phencyclidine binding by PPT. a Hill coefficient of approximately one was obtained in the presence of carbamylcholine and 0.8 in α-bungarotoxin-treated preparations. Taken together, these results indicate that PPt mimics phencyclidine in its ability to bind to the noncompetitive inhibitor site and is functionally active in blocking ion flux across the Acetylcholine Receptor channel. Analysis of the electron spin resonance signal of the bound PPT suggests that the environment surrounding the probe within the ion channel is hydrophobic, with a hydrophobicity parameter of 1.09. A dielectric constant for the binding site was estimated to be in the range of 2–3 units.
Catherine M. Garland - One of the best experts on this subject based on the ideXlab platform.
-
The actions of muscle relaxants at nicotinic Acetylcholine Receptor isoforms
European Journal of Pharmacology, 1998Co-Authors: Catherine M. Garland, Richard C. Foreman, John E. Chad, Lindy Holden-dye, Robert J. WalkerAbstract:The pharmacological diversity of the different isoforms of the nicotinic Acetylcholine Receptor arises from the diversity of the subunits that assemble to form the native Receptors. The aim of this study was to investigate the actions of the muscle relaxants d-tubocurarine, pancuronium and vecuronium on different isoforms of nicotinic Acetylcholine Receptors (mouse foetal muscle, mouse adult muscle and a rat neuronal), using the Xenopus oocyte expression system. Oocytes were injected with cRNAs for ?, ?, ?, ? subunits (the native foetal muscle subunit combination), or with cRNAs for ?, ?, , ? subunits (the native adult muscle subunit combination), or with cRNAs for ?4?2 subunits (a putative native neuronal subunit combination). Acetylcholine had a similar potency at all three subunit combinations (EC50 11.6, 17.4 and 19.1 ?M, respectively). At all three Receptor types, d-tubocurarine and pancuronium blocked the responses elicited by Acetylcholine in a reversible manner. Furthermore, the inhibition of the Acetylcholine currents for the foetal and adult nicotinic Acetylcholine Receptor by pancuronium and d-tubocurarine was independent of the holding voltage over the range ?100 to ?40 mV. In oocytes expressing the foetal muscle nicotinic Acetylcholine Receptors the inhibition of the current in response to 100 ?M Acetylcholine by 10 nM d-tubocurarine was 29±5% (mean±S.E.M.; n=7), and the inhibition by 10 nM pancuronium was 39±6% (mean±S.E.M.; n=8; P>0.05 vs. d-tubocurarine). However, in the adult form of the muscle nicotinic Acetylcholine Receptor, 10 nM d-tubocurarine and 10 nM pancuronium were both more effective at blocking the response to 100 ?M Acetylcholine compared to the foetal muscle nicotinic Acetylcholine Receptor, with values of 55±5% (P
-
The actions of muscle relaxants at nicotinic Acetylcholine Receptor isoforms
European journal of pharmacology, 1998Co-Authors: Catherine M. Garland, Richard C. Foreman, John E. Chad, Lindy Holden-dye, Robert J. WalkerAbstract:The pharmacological diversity of the different isoforms of the nicotinic Acetylcholine Receptor arises from the diversity of the subunits that assemble to form the native Receptors. The aim of this study was to investigate the actions of the muscle relaxants d-tubocurarine, pancuronium and vecuronium on different isoforms of nicotinic Acetylcholine Receptors (mouse foetal muscle, mouse adult muscle and a rat neuronal), using the Xenopus oocyte expression system. Oocytes were injected with cRNAs for alpha, beta, gamma, delta subunits (the native foetal muscle subunit combination), or with cRNAs for alpha, beta, epsilon, delta subunits (the native adult muscle subunit combination), or with cRNAs for alpha4beta2 subunits (a putative native neuronal subunit combination). Acetylcholine had a similar potency at all three subunit combinations (EC50 11.6, 17.4 and 19.1 microM, respectively). At all three Receptor types, d-tubocurarine and pancuronium blocked the responses elicited by Acetylcholine in a reversible manner. Furthermore, the inhibition of the Acetylcholine currents for the foetal and adult nicotinic Acetylcholine Receptor by pancuronium and d-tubocurarine was independent of the holding voltage over the range -100 to -40 mV. In oocytes expressing the foetal muscle nicotinic Acetylcholine Receptors the inhibition of the current in response to 100 microM Acetylcholine by 10 nM d-tubocurarine was 29 +/- 5% (mean +/- S.E.M.; n = 7), and the inhibition by 10 nM pancuronium was 39 +/- 6% (mean +/- S.E.M.; n = 8; P > 0.05 vs. d-tubocurarine). However, in the adult form of the muscle nicotinic Acetylcholine Receptor, 10 nM d-tubocurarine and 10 nM pancuronium were both more effective at blocking the response to 100 microM Acetylcholine compared to the foetal muscle nicotinic Acetylcholine Receptor, with values of 55 +/- 5% (P < 0.01; n = 12) and 60 +/- 4% (P < 0.001; n = 10), respectively. Thus the developmental switch from the gamma to the epsilon subunit alters the antagonism of the nicotinic Acetylcholine Receptor for both pancuronium and d-tubocurarine. Vecuronium was more potent than pancuronium. One nM vecuronium reduced the response to 100 microM Acetylcholine by 71 +- 6% (n = 10) for foetal and 63 +/- 5% (n = 4) for adult nicotinic Acetylcholine Receptors. In the alpha4beta2 neuronal nicotinic Acetylcholine Receptor combination, 10 nM pancuronium was a more effective antagonist of the response to 100 microM Acetylcholine (69 +/- 6%, n = 6) than 10 nM d-tubocurarine (30 +/- 5%; n = 6; P < 0.05 compared to pancuronium). This is in contrast to the adult muscle nicotinic Acetylcholine Receptor, where pancuronium and d-tubocurarine were equieffective. The expression of the beta2 subunit with muscle alpha, epsilon and delta subunits formed a functional Receptor which was blocked by pancuronium and d-tubocurarine in a similar manner to the alphabeta1epsilondelta subunit consistent with the hypothesis that the beta subunit is not a major determinant in the action of this drug at the adult muscle nicotinic Acetylcholine Receptor.
