Activation of alpha 7 Nicotinic Receptors By Anthelmintics Agents

BARTOS MARIANA; RAYES DIEGO; BOUZAT CECILIA

Pinamar. Argentina

Congreso; XX Reunión Anual Sociedad Argentina de Neuroquímica (SAN), XLI Reunión Anual SAIB, 10 th Congress Panamerican Association for Biochemistry and Molecular Biology (PABMB); 2005

SAN; SAIB; PABMB

Nicotinic acetylcholine receptors (AChRs) play key roles in chemical synapses. AChRs mediate neuromuscular transmission in nematodes and they are targets for antiparasitic drugs. The anthelmintic agents levamisole and pyrantel are potent agonists of nematode muscle AChRs but weak agonists of mammalian muscle AChRs. To understand the structural basis of the differential activation of anthelmintics among AChR subtypes, we studied the activation of  a7 AChRs by these agents at the single-channel and macroscopic-current level. We used the high conductance form of the a7-5HT3A receptor, which is a good model for pharmacological studies of a7. Macroscopic and unitary current recordings show that at a7 levamisole is a weak agonist, whereas pyrantel is more potent than ACh (EC50ACh= 200 µM, EC50pyr= 45 µM). To identify determinants of this differential activation, we replaced residues of the complementary face of the binding site by the equivalent in muscle e subunit and evaluated the kinetic changes. The mutation Q57G does not affect the activation by ACh. However, it increases the EC50 and decreases the maximal response elicited by pyrantel. Single channels can be detected at 10-fold higher concentrations and the duration of bursts of openings significantly decreases with respect to the control chimera. The decreased sensitivity of Q57G-a7 to pyrantel agrees with its weak action at muscle AChRs, indicating that this residue may be involved in the differential activation of AChR subtypes by pyrantel.