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.