Antagonist activities of mecamylamine and nicotine show reciprocal dependence on beta subunit sequence in the second transmembrane domain

摘要: 1 We show that a portion of the TM2 domain regulates sensitivity beta subunit-containing rat neuronal nicotinic AChR to ganglionic blocker mecamylamine, such substitution 4 amino acids muscle subunit sequence into beta4 decreases potency mecamylamine by factor 200 and eliminates any long-term eAects this drug on receptor function. 2 The same exchange inhibition produces comparable potentiation nicotine. 3 Inhibition is voltage-dependent, suggesting direct interaction with elements within membrane field. have previously shown TMP (tetramethylpiperidine) inhibitors controlled determine sensitivity. However, bis-TMP compounds independent voltage. Our experiments did not influence voltage chimeric receptors nicotine, inhibitory nicotine are mediated binding site outside membrane’s electric 5 An analysis point mutations indicates residues at 6’ position may be important for determining both in reciprocal manner. Single 10’ suAcient produce eAects, but double mutants more eAect than do single mutants.