Correlation of agonist structure with acetylcholine receptor kinetics: studies on the frog end-plate and on chick embryo muscle.
The apparent lifetimes of frog end-plate channels activated by several nicotinic agonists have been determined with voltage-jump and fluctuation analysis techniques. The agonists were monoquaternary, N-substituted derivatives of trimethylammonium (TMA). Methyl TMA activated channels which had apparent lifetimes about 3-4 times shorter than acetylcholine (ACh)-activated channels. This result was confirmed with single-channel recordings from embryonic chick skeletal muscle. Channel conductance and voltage dependence of channel lifetime were similar for methyl TMA- and ACh-activated channels. Methyl TMA showed no signs of blocking open end-plate channels. Ethyl TMA, acetylthiocholine, cholinethiol and carbamylcholine all activated channels similar to methyl TMA-activated channels with regard to lifetime. None of these agonists appeared to block end-plate channels in the employed concentrations. 4-ketopentyl TMA, which contains a methylene group in place of the ether oxygen of ACh, sometimes opened end-plate channels with similar apparent lifetimes as those opened by ACh. Single-channel recordings showed that bursts of current from channels activated by 4-ketopentyl TMA have similar durations as do those activated by ACh. Pentyl TMA and benzyl TMA block open end-plate channels even when delivered at doses which elicit very small currents. It is concluded that the ester moiety of ACh serves to stabilize the open conformation of the channel.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002642:Chick Embryo; D004594:Electrophysiology; D007473:Ion Channels / Q000187:drug effects; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009045:Motor Endplate / Q000502:physiology*; D009132:Muscles / Q000196:embryology / Q000502:physiology*; D009469:Neuromuscular Junction / Q000502:physiology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D011894:Rana pipiens; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors
D007473:Ion Channels; D000644:Quaternary Ammonium Compounds; D011978:Receptors, Nicotinic; D000109:Acetylcholine