title: Is agonist self-inhibition at the nicotinic acetylcholine receptor a nonspecific action?
abstract: Agonist concentration-response relationships at nicotinic postsynaptic receptors were established by measuring 86Rb+ efflux from acetylcholine receptor rich native Torpedo membrane vesicles under three different conditions: integrated net ion efflux (in 10 s) from untreated vesicles, integrated net efflux from vesicles in which most acetylcholine sites were irreversibly blocked with alpha-bungarotoxin, and initial rates of efflux (5-100 ms) from vesicles that were partially blocked with alpha-bungarotoxin. Exposure to acetylcholine, carbamylcholine, suberyldicholine, phenyltrimethylammonium, or (-)-nicotine over 10(8)-fold concentration ranges results in bell-shaped ion flux response curves due to stimulation of acetylcholine receptor channel opening at low concentrations and inhibition of channel function at 60-2000 times higher concentrations. Concentrations of agonists that inhibit their own maximum 86Rb+ efflux by 50% (KB values) are 110, 211, 3.0, 39, and 8.9 mM, respectively, for the agonists listed above. For acetylcholine and carbamylcholine, KB values determined from both 10-s and 15-ms efflux measurements are the same, indicating that the rate of agonist-induced desensitization increases to maximum at concentrations lower than those causing self-inhibition. For all partial and full agonists studied, Hill coefficients for self-inhibition are close to 1.0. Concentrations of agonists up to 8 times KB did not change the order parameter reported by a spin-labeled fatty acid incorporated in Torpedo membranes. We conclude that agonist self-inhibition cannot be attributed to a general nonspecific membrane perturbation. Instead, these results are consistent with a saturable site of action either at the lipid-protein interface or on the acetylcholine receptor protein itself.
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology; D004557:Electric Organ / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D007531:Isoflurophate / Q000494:pharmacology; D007700:Kinetics; D009538:Nicotine / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D012413:Rubidium / Q000378:metabolism; D013570:Synaptic Membranes / Q000378:metabolism*; D014101:Torpedo
chemical_list: D000644:Quaternary Ammonium Compounds; D011978:Receptors, Nicotinic; D007531:Isoflurophate; C009571:phenyltrimethylammonium; C009335:subecholine; D009538:Nicotine; D002217:Carbachol; D012413:Rubidium; D002794:Choline; D000109:Acetylcholine