Effect of the anthelmintic agent levamisole on mammalian nicotinic acetylcholine receptors

D. RAYES,; M.J. DE ROSA,; M. BARTOS,; CECILIA BEATRIZ BOUZAT

San Carlos de Bariloche

Congreso; XXXIX Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular y XXXII Reunión Anual de la Sociedad Argentina de Biofísica - Bariloche Protein Symposium; 2003

  EFFECT OF THE ANTHELMINTIC AGENT LEVAMISOLE ON MAMMALIAN NICOTINIC RECEPTORS   Diego Rayes, María José De Rosa, Mariana Bartos and Cecilia Bouzat Instituto de Investigaciones Bioquímicas, UNS-CONICET, Bahía Blanca, Argentina. e-mail: drayes@criba.edu.ar   Levamisole is an anthelmintic agent that exerts its therapeutic effects by acting as a full agonist of nicotinic receptors (AChR) of muscle nematodes. We explore at the single-channel and  macroscopic-current levels the action of levamisole on mammalian muscle AChR. Levamisole is capable of activating mammalian AChRs. However, single-channel openings do not appear in clearly identifiable clusters at high concentrations. In addition, levamisol activation is not enough to elicit macroscopic currents. Both findings suggest that levamisole acts as a weak agonist of mammalian AChRs. In the presence of levamisol the channel mean open time decreases as a function of concentration (7-fold at 100 µM), indicating an additional open-channel block (Kd 140 mM at -70 mV). Sequence alignment of mammalian and nematode AChR shows several non conserved residues which might be candidates for the differential activation by levamisole. The replacement of the conserved glycine at position 153 in the a subunit by its homologous in the parasite (aG153E) allows levamisole to produce identifiable clusters, thus making mammalian AChRs more sensitive to levamisole activation. We show that levamisole is a weak agonist and a open-channel blocker of mammalian AChRs and that the glutamic acid at position 153 is important for the behavior of the anthelmintic on the parasite AChR.