Vijverberg HP

References (7)

Title : Cholinergic drugs potentiate human nicotinic alpha4beta2 acetylcholine receptors by a competitive mechanism - Smulders_2005_Eur.J.Pharmacol_509_97
Author(s) : Smulders CJ , Zwart R , Bermudez I , van Kleef RG , Groot-Kormelink PJ , Vijverberg HP
Ref : European Journal of Pharmacology , 509 :97 , 2005
Abstract : Effects of cholinergic drugs on human alpha4beta2 nicotinic acetylcholine receptors expressed in Xenopus oocytes have been investigated in electrophysiological and ligand binding experiments. Atropine, scopolamine, physostigmine, and tacrine combine potentiation of ion current induced by low concentrations of acetylcholine with inhibition of ion current evoked by high concentrations of acetylcholine. Rivastigmine, galanthamine, and dichlorvos cause only inhibition of ion current evoked by low concentrations of acetylcholine. Binding experiments show that the potentiating cholinergic drugs atropine, scopolamine, and physostigmine are competitive ligands of human alpha4beta2 nicotinic acetylcholine receptors. Conversely, the inhibitory cholinergic drugs galanthamine and rivastigmine are non-competitive. The non-competitive drugs are not allosteric, since they do not affect the saturation curve of the radioligand [3H]cytisine. Effects of potentiating cholinergic drugs on nicotinic acetylcholine receptors are consistent with and predicted by a model comprising competitive drug effects at two equivalent agonist recognition sites on the nicotinic acetylcholine receptor combined with non-competitive ion channel block.
ESTHER : Smulders_2005_Eur.J.Pharmacol_509_97
PubMedSearch : Smulders_2005_Eur.J.Pharmacol_509_97
PubMedID: 15733544

Title : A noncompetitive, sequential mechanism for inhibition of rat alpha4beta2 neuronal nicotinic acetylcholine receptors by carbamate pesticides - Smulders_2004_Toxicol.Sci_82_219
Author(s) : Smulders CJ , van Kleef RG , de Groot A , Gotti C , Vijverberg HP
Ref : Toxicol Sci , 82 :219 , 2004
Abstract : The mechanism by which carbamate pesticides inhibit rat alpha4beta2 nicotinic acetylcholine (ACh) receptors (nAChRs) expressed in Xenopus laevis oocytes has been investigated using the two-electrode voltage clamp technique. Carbaryl, S-ethyl N,N-dipropylthiocarbamate (EPTC), and fenoxycarb inhibit ACh-induced ion currents in a concentration-dependent way. EPTC and fenoxycarb inhibit ion currents induced by 1 mM ACh with 3-fold to 5-fold higher potency than ion currents induced by 1 microM ACh. The potency of carbaryl appears to be independent of ACh concentration. Fenoxycarb displaces (3)H-epibatidine bound to alpha4beta2 (nAChRs) with a K(i) of 750 microM, which is much higher than the functional IC(50) of 2.3-11 microM. This shows that the inhibition of ion current by the carbamate is a noncompetitive effect. Inhibition by fenoxycarb is independent of the state of the ion channel. The rate of onset of inhibition is enhanced, and the rate of reversal of inhibition is reduced, when the concentration of fenoxycarb is increased. The rate of reversal of inhibition is also reduced when the period of exposure to fenoxycarb is increased. The time- and concentration-dependent inhibition of nAChR-mediated ion current by fenoxycarb is accounted for by a two-step mechanism involving a rapid blocked state and a sequential more stably blocked or desensitized state.
ESTHER : Smulders_2004_Toxicol.Sci_82_219
PubMedSearch : Smulders_2004_Toxicol.Sci_82_219
PubMedID: 15329441

Title : Block of neuronal nicotinic acetylcholine receptors by organophosphate insecticides - Smulders_2004_Toxicol.Sci_82_545
Author(s) : Smulders CJ , Bueters TJ , Vailati S , van Kleef RG , Vijverberg HP
Ref : Toxicol Sci , 82 :545 , 2004
Abstract : Chronic and acute exposure to organophosphate (OP) pesticides may lead to persistent neurological and neurobehavioral effects, which cannot be explained by acetylcholinesterase (AChE) inhibition alone. It is suggested that other brain proteins are involved. Effects of commonly used organophosphate pesticides on rat neuronal alpha4beta2 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. Several OP pesticides, e.g., parathion-ethyl, chlorpyrifos and disulfoton, inhibited the ACh-induced ion current with potencies in the micromolar range. The potency of inhibition increased with increasing concentrations of the agonist ACh. Comparison of the potency of nAChR inhibition with the potency of AChE inhibition demonstrated that some OPs inhibit nAChRs more potently than AChE. Binding experiments on alpha4beta2 nAChRs showed that the OPs noncompetitively interact with nAChRs. The inhibitory effects on nAChRs are adequately described and explained by a sequential two-step mechanism, in which rapidly reversible OP binding to a separate binding site leads to inhibition followed by a stabilization of the blocked state or receptor desensitization. It is concluded that OPs interact directly with neuronal alpha4beta2 nAChRs to inhibit the agonist-induced response. This implicates that neuronal alpha4beta2 nAChRs are additional targets for some OP pesticides.
ESTHER : Smulders_2004_Toxicol.Sci_82_545
PubMedSearch : Smulders_2004_Toxicol.Sci_82_545
PubMedID: 15342957

Title : Effects of carbamate insecticides on rat neuronal alpha4beta4 nicotinic receptors and rat brain acetylcholinesterase. -
Author(s) : Smulders C , Bueters TJ , van Kleef RG , Vijverberg HP
Ref : Cholinergic Mechanisms, CRC Press :715 , 2004
PubMedID:

Title : Selective effects of carbamate pesticides on rat neuronal nicotinic acetylcholine receptors and rat brain acetylcholinesterase - Smulders_2003_Toxicol.Appl.Pharmacol_193_139
Author(s) : Smulders CJ , Bueters TJ , van Kleef RG , Vijverberg HP
Ref : Toxicol Appl Pharmacol , 193 :139 , 2003
Abstract : Effects of commonly used carbamate pesticides on rat neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. The potencies of these effects have been compared to the potencies of the carbamates to inhibit rat brain acetylcholinesterase. The potency order of six carbamates to inhibit alpha4beta4 nicotinic receptors is fenoxycarb > EPTC > carbaryl, bendiocarb > propoxur > aldicarb with IC50 values ranging from 3 microM for fenoxycarb to 165 microM for propoxur and >1 mM for aldicarb. Conversely, the potency order of these carbamates to inhibit rat brain acetylcholinesterase is bendiocarb > propoxur, aldicarb > carbaryl > EPTC, fenoxycarb with IC50 values ranging from 1 microM for bendiocarb to 17 microM for carbaryl and > mM for EPTC and fenoxycarb. The alpha4beta2, alpha3beta4, and alpha3beta2 nicotinic acetylcholine receptors are inhibited by fenoxycarb, EPTC, and carbaryl with potency orders similar to that for alpha4beta4 receptors. Comparing the potencies of inhibition of the distinct subtypes of nicotinic acetylcholine receptors shows that the alpha3beta2 receptor is less sensitive to inhibition by fenoxycarb and EPTC. The potency of inhibition depends on the carbamate as well as on a combination of alpha and beta subunit properties. It is concluded that carbamate pesticides affect different subtypes of neuronal nicotinic receptors independently of acetylcholinesterase inhibition. This implicates that neuronal nicotinic receptors are additional targets for some carbamate pesticides and that these receptors may contribute to carbamate pesticide toxicology, especially after long-term exposure.
ESTHER : Smulders_2003_Toxicol.Appl.Pharmacol_193_139
PubMedSearch : Smulders_2003_Toxicol.Appl.Pharmacol_193_139
PubMedID: 14644616

Title : Potentiation and inhibition of neuronal alpha4beta4 nicotinic acetylcholine receptors by choline - Zwart_2000_Eur.J.Pharmacol_393_209
Author(s) : Zwart R , Vijverberg HP
Ref : European Journal of Pharmacology , 393 :209 , 2000
Abstract : The effects of choline on alpha4beta4 nicotinic acetylcholine receptors, expressed in Xenopus oocytes, were investigated using in the two-microelectrode voltage clamp technique. Particular attention was paid to the interaction between the effects of acetylcholine and choline. Choline was a low-affinity agonist of alpha4beta4 receptors with an efficacy of 10% as compared to acetylcholine. Responses evoked by 1 microM acetylcholine were potentiated by low concentrations of choline and inhibited by > 10mM choline, resulting in a bell-shaped concentration-effect relationship. Conversely, the effects of choline on responses evoked by 300 microM acetylcholine resulted in a monophasic inhibition curve with an IC(50) of 0.87 mM. The data were fitted by a two-site receptor occupation model, which accounts for similar effects of various cholinergic ligands on heteromeric nicotinic receptors. The results indicate that the potentiation was a competitive effect, whereas the inhibition was due to a mixture of competitive and non-competitive effects. It is concluded that choline acts as a potent, endogenous co-agonist at heteromeric alpha4beta4 nicotinic receptors.
ESTHER : Zwart_2000_Eur.J.Pharmacol_393_209
PubMedSearch : Zwart_2000_Eur.J.Pharmacol_393_209
PubMedID: 10771015

Title : Competitive potentiation of acetylcholine effects on neuronal nicotinic receptors by acetylcholinesterase-inhibiting drugs - Zwart_2000_J.Neurochem_75_2492
Author(s) : Zwart R , van Kleef RG , Gotti C , Smulders CJ , Vijverberg HP
Ref : Journal of Neurochemistry , 75 :2492 , 2000
Abstract : The effects of the acetylcholinesterase inhibitors physostigmine and tacrine on alpha4beta2 and alpha4beta4 subtypes of neuronal nicotinic acetylcholine (ACh) receptors, expressed in Xenopus laevis oocytes, have been investigated. In voltage-clamp experiments low concentrations of physostigmine and tacrine potentiate ion currents induced by low concentrations of ACh, whereas at high concentrations they inhibit ACh-induced ion currents. These dual effects result in bell-shaped concentration-effect curves. Physostigmine and tacrine, by themselves, do not act as nicotinic receptor againsts. The larger potentiation is observed with 10 microM: physostigmine on alpha4beta4 nicotinic receptors and amounts to 70% at 1 microM: ACh. The mechanism underlying the effects of physostigmine on alpha4beta4 ACh receptors has been investigated in detail. Potentiation of ACh-induced ion current by low concentrations of physostigmine is surmounted at elevated concentrations of ACh, indicating that this is a competitive effect. Conversely, inhibition of ACh-induced ion current by high concentrations of physostigmine is not surmounted at high concentrations of ACh, and this effect appears mainly due to noncompetitive, voltage-dependent ion channel block. Radioligand binding experiments demonstrating displacement of the nicotinic receptor agonist (125)I-epibatidine from its recognition sites on alpha4beta4 ACh receptors by physostigmine confirm that physostigmine is a competitive ligand at these receptors. A two-site equilibrium receptor occupation model, combined with noncompetitive ion channel block, accounts for the dual effects of physostigmine and tacrine on ACh-induced ion currents. It is concluded that these acetylcholinesterase-inhibiting drugs interact with the ACh recognition sites and are coagonists of ACh on alpha4-containing nicotinic ACh receptors.
ESTHER : Zwart_2000_J.Neurochem_75_2492
PubMedSearch : Zwart_2000_J.Neurochem_75_2492
PubMedID: 11080202