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Differential effects of physostigmine and organophosphates on nicotinic receptors in neuronal cells of different species.
Neurotoxicology. 1998 Dec; 19(6):777-87.N

Abstract

The effects of the carbamate physostigmine and of the organophosphates (OPs) parathion, paraoxon and phenyl saligenin cyclic phosphate (PSP) were examined on different subtypes of neuronal nicotinic acetylcholine receptors (nAChR). Stimulation with 1 mM ACh induced transient nicotinic inward currents in mouse N1E-115 and human SH-SY5Y neuroblastoma and in locust thoracic ganglion cells. All four acetylcholinesterase (AChE) inhibitors reduced the nicotinic currents in a concentration-dependent manner. Parathion is about 50 times more potent in blocking nAChR, compared to its active AChE inhibiting metabolite paraoxon. The relative blocking potency of the different AChE inhibitors was the same in all cell types, and followed the order parathion > physostigmine > PSP > paraoxon. In N1E-115 cells the IC50 values of block amounted to 2 microM, 30 microM, 39 microM and 96 microM for parathion, physostigmine, PSP and paraoxon, respectively. In all cell types, the nicotinic currents were equally blocked by parathion. Human nAChR in SH-SY5Y cells appeared more sensitive to block by physostigmine, PSP and paraoxon, while these AChE inhibitors similarly inhibited nicotinic currents in insect cells and in mouse neuroblastoma cells. The observation that the concentration-dependence of block is different from that of AChE inhibition, indicates a distinct interaction of AChE inhibitors with nAChR. Only in locust cells physostigmine induced a non-desensitizing inward current, that appeared to originate from nAChR activation. Occasionally, the OPs were able to activate slow ionic currents in mouse, but not in human and locust cells. As the OP-induced agonistic activity in mouse cells was not associated with the blocking action, the target site appeared to be distinct from nAChR. These results show that AChE inhibitors block nAChR with different potencies, dependent on the compound and the receptor subtype, and may activate distinct ion currents in neuronal cells of different species origin.

Authors+Show Affiliations

Research Institute of Toxicology, Utrecht University, The Netherlands.No affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

9863767

Citation

van den Beukel, I, et al. "Differential Effects of Physostigmine and Organophosphates On Nicotinic Receptors in Neuronal Cells of Different Species." Neurotoxicology, vol. 19, no. 6, 1998, pp. 777-87.
van den Beukel I, van Kleef RG, Oortgiesen M. Differential effects of physostigmine and organophosphates on nicotinic receptors in neuronal cells of different species. Neurotoxicology. 1998;19(6):777-87.
van den Beukel, I., van Kleef, R. G., & Oortgiesen, M. (1998). Differential effects of physostigmine and organophosphates on nicotinic receptors in neuronal cells of different species. Neurotoxicology, 19(6), 777-87.
van den Beukel I, van Kleef RG, Oortgiesen M. Differential Effects of Physostigmine and Organophosphates On Nicotinic Receptors in Neuronal Cells of Different Species. Neurotoxicology. 1998;19(6):777-87. PubMed PMID: 9863767.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential effects of physostigmine and organophosphates on nicotinic receptors in neuronal cells of different species. AU - van den Beukel,I, AU - van Kleef,R G, AU - Oortgiesen,M, PY - 1998/12/24/pubmed PY - 1998/12/24/medline PY - 1998/12/24/entrez SP - 777 EP - 87 JF - Neurotoxicology JO - Neurotoxicology VL - 19 IS - 6 N2 - The effects of the carbamate physostigmine and of the organophosphates (OPs) parathion, paraoxon and phenyl saligenin cyclic phosphate (PSP) were examined on different subtypes of neuronal nicotinic acetylcholine receptors (nAChR). Stimulation with 1 mM ACh induced transient nicotinic inward currents in mouse N1E-115 and human SH-SY5Y neuroblastoma and in locust thoracic ganglion cells. All four acetylcholinesterase (AChE) inhibitors reduced the nicotinic currents in a concentration-dependent manner. Parathion is about 50 times more potent in blocking nAChR, compared to its active AChE inhibiting metabolite paraoxon. The relative blocking potency of the different AChE inhibitors was the same in all cell types, and followed the order parathion > physostigmine > PSP > paraoxon. In N1E-115 cells the IC50 values of block amounted to 2 microM, 30 microM, 39 microM and 96 microM for parathion, physostigmine, PSP and paraoxon, respectively. In all cell types, the nicotinic currents were equally blocked by parathion. Human nAChR in SH-SY5Y cells appeared more sensitive to block by physostigmine, PSP and paraoxon, while these AChE inhibitors similarly inhibited nicotinic currents in insect cells and in mouse neuroblastoma cells. The observation that the concentration-dependence of block is different from that of AChE inhibition, indicates a distinct interaction of AChE inhibitors with nAChR. Only in locust cells physostigmine induced a non-desensitizing inward current, that appeared to originate from nAChR activation. Occasionally, the OPs were able to activate slow ionic currents in mouse, but not in human and locust cells. As the OP-induced agonistic activity in mouse cells was not associated with the blocking action, the target site appeared to be distinct from nAChR. These results show that AChE inhibitors block nAChR with different potencies, dependent on the compound and the receptor subtype, and may activate distinct ion currents in neuronal cells of different species origin. SN - 0161-813X UR - https://www.unboundmedicine.com/medline/citation/9863767/Differential_effects_of_physostigmine_and_organophosphates_on_nicotinic_receptors_in_neuronal_cells_of_different_species_ DB - PRIME DP - Unbound Medicine ER -