TY - JOUR T1 - Inhibition of Wild-Type and Mutant Neuronal Nicotinic Acetylcholine Receptors by Local Anesthetics JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1365 LP - 1374 DO - 10.1124/mol.60.6.1365 VL - 60 IS - 6 AU - Roger L. Papke AU - Benjamin A. Horenstein AU - Andon N. Placzek Y1 - 2001/12/01 UR - http://molpharm.aspetjournals.org/content/60/6/1365.abstract N2 - Inhibition of neuronal nicotinic receptors can be regulated by the presence of specific amino acids in the β subunit second transmembrane domain (TM2) domain. We show that the incorporation of a mutant β4 subunit, which contains sequence from the muscle β subunit at the TM2 6′ and 10′ positions of the neuronal β4 subunit, greatly reduces the sensitivity of receptors to the local anesthetic [2-(triethylamino)-N-(2,6-dimethylphenyl)acetamide] (QX-314). Although differing in potency, the inhibition of both wild-type α3β4 receptors and α3β4(6′F10′T) receptors by QX-314 is voltage-dependent and noncompetitive. Interestingly, the potency of the local anesthetic tetracaine for the inhibition of α3β4 and α3β4(6′F10′T) receptors seems unchanged when measured at −50 mV. However, whereas the onset of inhibition of wild-type α3β4 receptors is voltage-dependent and noncompetitive, the onset of inhibition of α3β4(6′F10′T) receptors by tetracaine is unaffected by membrane voltage, and at concentrations ≤30 μM seems to be competitive with acetylcholine. This may be due to either direct effects of tetracaine at the acetylcholine binding site or preferential block of closed rather than open channels in the mutant receptors. Further analysis of receptors containing the 6′ mutation alone suggests that although the 6′ mutation is adequate to alter the voltage dependence of tetracaine inhibition, both point mutations are required to produce the apparent competitive effects. ER -