Differential effects of physostigmine and organophosphates on nicotinic receptors in neuronal cells of different species

The effects of the carbamate physostigmine and of the organophosphates (OPs ) parathion, paraoxon and phenyl saligenin cyclic phosphate (PSP) were exam ined on different subtypes of neuronal nicotinic acetylcholine receptors (n AChR). Stimulation with 1 mM ACh induced transient nicotinic inward current s in mouse N1E-115 and human SH-SY5Y neuroblastoma and in locust thoracic g anglion 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 inhibit ing metabolite paraoxon. The relative blocking potency of the different ACh E inhibitors was the same in all cell types, and followed the order parathi on > physostigmine > PSP > paraoxon. In N1E-115 cells the IC50 values of bl ock amounted to 2 mu M, 30 mu M, 39 mu M and 96 mu M for parathion, physost igmine, PSP and paraoxon, respectively. in all cell types, the nicotinic cu rrents were equally blocked by parathion. Human nAChR in SH-SY5Y cells appe ared more sensitive to block by physostigmine, PSF and paraoxon, while thes e AChE inhibitors similarly inhibited nicotinic currents in insect cells an d in mouse neuroblastoma cells. The observation that the concentration-depe ndence of block is different from that of AChE inhibition, indicates a dist inct interaction of AChE inhibitors with nAChR. Only in locust cells physos tigmine induced a non-desensitizing inward current, that appeared to origin ate from nAChR activation. Occasionally, the OPs were able to activate slow ionic currents in mouse, but not in human and locust cells. As the OF-indu ced agonistic activity in mouse cells was not associated with the blocking action, the target site appeared to be distinct from nAChR. These results s how that AChE inhibitors block nAChR with different potencies, dependent on the compound and the receptor subtype, and may activate distinct ion curre nts in neuronal cells of different species origin. (C) 1998 Intox Press, In c.