Received for publication May 5, 2006.
Revised July 4, 2006.
Accepted for publication July 5, 2006.

MOLECULAR DETERMINANTS OF PYRANTEL SELECTIVITY IN NICOTINIC RECEPTORS

Abstract

Nicotinic receptors (AChRs) play key roles in synaptic transmission throughout the nervous system. AChRs mediate neuromuscular transmission in nematodes and they are targets for antiparasitic drugs. The anthelmintic agents levamisole and pyrantel, which are potent agonists of nematode muscle AChRs, are partial agonists of mammalian muscle AChRs. To further explore the structural basis of the differential activation of AChR subtypes by anthelmintics, we studied the activation of 7 AChRs using the high conductance form of the 7-5HT_3A receptor, which is a good model for pharmacological studies involving the extracellular region of 7. Macroscopic and single-channel current recordings show that levamisole is a weak agonist of 7. Interestingly, pyrantel is a more potent agonist of 7 than ACh. To identify determinants of this differential activation, we replaced residues of the complementary face of the binding site by the homologous residues in the muscle subunit and evaluated changes in activation. The mutation Q57G does not affect the activation by either ACh or levamisole. However, it increases EC₅₀ and decreases the maximal response to pyrantel. Kinetic analysis shows that gating of the mutant channel activated by pyrantel is profoundly impaired. The decreased sensitivity of 7-Q57G to pyrantel agrees with its weak action at muscle AChRs, indicating that when glycine occupies position 57, as in the mammalian muscle AChR, pyrantel behaves as a partial agonist. Thus, position 57 located at the complementary face of the binding site plays a key role in the selective activation of AChRs by pyrantel.

Key words: Nicotinic cholinergic, Mutagenesis/Chimeric approaches, Single channel kinetics

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