Aim: 

Lidocaine has multiple inhibitory actions on nicotinic acetylcholine receptors (nAChRs). To dissect the structural determinants of lidocaine blockade of nAChRs, we studied the effects of both diethylamine (DEA) and 2,6-dimethylaniline (DMA), which resemble lidocaine's hydrophilic and hydrophobic moieties, respectively.

Methods: 

Torpedo nAChRs were transplanted to Xenopus oocytes and currents elicited by ACh (I_ACh), either alone or co-applied with either DEA or DMA, were recorded.

Results: 

I_ACh was reversibly blocked by both DEA and DMA, but with marked differences in their mechanisms of inhibition. The dose-inhibition curve for DEA was similar to that found for lidocaine (IC₅₀ close to 100 mM; Hill coefficient, 1), whereas for DMA the IC₅₀ was in the millimolar range. Like lidocaine, DEA blockade of I_ACh was only present at negative potentials and showed a non-competitive behaviour, suggesting an open-channel blockade; nevertheless, the electrical distances obtained for lidocaine and DEA were different. In contrast, DMA, a hydrophobic molecule, showed a rather voltage-independent blockade of nAChRs and, besides, increased their desensitization rate.

Conclusions: 

These results indicate that the hydrophilic region of lidocaine accounts for the open-channel blockade of nAChRs, whereas the hydrophobic end is responsible for the voltage-independent blockade and the increase in desensitization.

This work was partially supported by DGICYT grant BFU2006-04781 (Spain).