Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors.
From: Instituto de Investigaciones Bioquímicas, Universidad Nacional del Sur-Consejo de Investigaciones Científicas y Técnicas, Camino La Carrindanga Km 7, B8000FWB, Bahía Blanca, Argentina.
Molecular pharmacology
- Publish Date: Oct 2006
- ISSN: 0026-895X
- Volume: 70
- Issue: 4
- Pages: 1307-18
- Medium: Print
- Language: English
- Citation (JAMA): Bartos Mariana, Rayes Diego, Bouzat Cecilia, et al. Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors.. Mol. Pharmacol. Oct 2006;70:1307-18
Abstract
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 alpha7 AChRs using the high-conductance form of the alpha7-5-hydroxytryptamine-3A receptor, which is a good model for pharmacological studies involving the extracellular region of alpha7. Macroscopic and single-channel current recordings show that levamisole is a weak agonist of alpha7. It is interesting that pyrantel is a more potent agonist of alpha7 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 epsilon 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 alpha7-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.
Mesh Headings (Keywords): Acetylcholine, Amino Acid Sequence, Animals, Anthelmintics, Binding Sites, Humans, Levamisole, Membrane Potentials, Models, Biological, Molecular Sequence Data, Nicotinic Agonists, Pyrantel, Receptors, Nicotinic, Receptors, Serotonin, Sequence Homology, Amino Acid
Check for Full Text / PubMed Unique Identifier (PMID): 16825485
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.