DESENSITIZATION OF ACETYLCHOLINE RECEPTOR BY THE LOCAL ANESTHETIC PROADIFEN.

SPITZMAUL, GUILLERMO; GUMILAR, FERNANDA; DILGER, JAMES P.; BOUZAT, CECILIA

San Carlos de Bariloche

Congreso; XXXIX Annual Meeting of Sociedad Argentina de Investigación Bioquímica y Biología Molecular and XXXII Annual Meeting of Sociedad Argentina de Biofísica; 2003

SAIB and SAB

The nicotinic receptor (AChR) of adult muscle is composed of five subunits in the order a2bed. Non competitive inhibitors (NCI) decrease the probability of channel opening by different mechanisms. The binding site for proadifen has been located at the extracellular end of the M2 domain. To elucidate the mechanism of action of proadifen on the AChR we made single-channel and macroscopic current recordings. Single-channel recordings reveal a decrease in the frequency of openings events without significant changes in the mean open time of the channel. This observation is compatible with an increase in desensitization rate from the open or closed state. At high ACh concentrations clusters of openings in the presence of proadifen were similar to those of the control, suggesting that proadifen is affecting the closed state. We also studied macroscopic currents activated by rapid application of ACh. Proadifen decreases the peak current without changing the decay rate due to desensitization. Preincubation with proadifen is necessary for its maximal pharmacological  effect. Our results reveal that proadifen desensitizes AChRs that are in the closed state and neither affects open AChRs nor acts as an open-channel blocker.