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