PT  - JOURNAL ARTICLE
AU  - Mariana Bartos
AU  - Diego Rayes
AU  - Cecilia Bouzat
TI  - Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors
AID  - 10.1124/mol.106.026336
DP  - 2006 Oct 01
TA  - Molecular Pharmacology
PG  - 1307--1318
VI  - 70
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/70/4/1307.short
4100  - http://molpharm.aspetjournals.org/content/70/4/1307.full
SO  - Mol Pharmacol2006 Oct 01; 70
AB  - Nicotinic receptors (acetylcholine 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 α7 AChRs using the high-conductance form of the α7-5-hydroxytryptamine-3A receptor, which is a good model for pharmacological studies involving the extracellular region of α7. Macroscopic and single-channel current recordings show that levamisole is a weak agonist of α7. It is interesting that pyrantel is a more potent agonist of α7 than acetylcholine (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 ϵ subunit and evaluated changes in activation. The mutation Q57G does not affect the activation by either ACh or levamisole. However, it increases EC50 values 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 α7-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. The American Society for Pharmacology and Experimental Therapeutics