Studies were conducted to ascertain the temporal and dose-dependent effects of 
nicotinic ligand exposure on functional activity of different nicotinic 
acetylcholine receptor (nAChR) subtypes, as expressed by cells of the PC12 rat 
pheochromocytoma (ganglia-type nAChR) or the TE671/RD human (muscle-type nAChR) 
clonal line. Chronic (3-72-h) agonist (nicotine or carbamylcholine) treatment of 
cells led to a complete (TE671) or nearly complete (PC12) loss of functional 
nAChR responses, which is referred to as "functional inactivation." Some 
inactivation of nAChR function was also observed for the nicotinic ligands 
d-tubocurarine (d-TC), mecamylamine, and decamethonium. Half-maximal 
inactivation of nAChR function was observed within 3 min for TE671 cells and 
within 10 min for PC12 cells treated with inactivating ligands. Functional 
inactivation occurred with dose dependencies that could not always be reconciled 
with those obtained for acute agonist activation of nAChR function or for acute 
inhibition of those responses by d-TC, decamethonium, or mecamylamine. Treatment 
of TE671 or PC12 cells with the nicotinic antagonist pancuronium or alcuronium 
alone had no effect on levels of expression of functional nAChRs. However, 
evidence was obtained that either of these antagonists protected TE671 cell 
muscle-type nAChRs or PC12 cell ganglia-type nAChRs from functional inactivation 
on long-term treatment with agonists. Recovery of TE671 cell nAChR function 
following treatment with carbamylcholine, nicotine, or d-TC occurred with 
half-times of 1-3 days whether cells were maintained in situ or harvested and 
replated after removal of ligand. By contrast, 50% recovery of functional nAChRs 
on PC12 cells occurred within 2-6 h after drug removal. In either case the time 
course for recovery from nAChR functional inactivation is much slower than 
recovery from nAChR "functional desensitization," which is a reversible process 
that occurs on shorter-term (0-5-min) agonist exposure of cells. These results 
indicate that ganglia-type and muscle-type nAChRs are similar in their 
sensitivities to functional inactivation by nicotinic ligands but differ in 
their rates of recovery from and onset of those effects. The ability of drugs 
such as the agonists d-TC, decamethonium, and mecamylamine to induce functional 
inactivation may relate to their activities as partial/full agonists, channel 
blockers, and/or allosteric regulators. Effects of drugs such as pancuronium and 
alcuronium are likely to reflect simple competitive inhibition of primary ligand 
binding at functional activation sites.(ABSTRACT TRUNCATED AT 400 WORDS)