On the nature of partial agonism in the nicotinic receptor superfamily.
Partial agonists are ligands that bind to receptors but produce only a small maximum response even at concentrations where all receptors are occupied. In the case of ligand-activated ion channels, it has been supposed since 1957 that partial agonists evoke a small response because they are inefficient at eliciting the change of conformation between shut and open states of the channel. We have investigated partial agonists for two members of the nicotinic superfamily-the muscle nicotinic acetylcholine receptor and the glycine receptor-and find that the open-shut reaction is similar for both full and partial agonists, but the response to partial agonists is limited by an earlier conformation change ('flipping') that takes place while the channel is still shut. This has implications for the interpretation of structural studies, and in the future, for the design of partial agonists for therapeutic use.
Lape
Remigijus
R
Department of Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK.
Colquhoun
David
D
Sivilotti
Lucia G
LG
D000818:Animals; D002460:Cell Line; D054333:Drug Partial Agonism; D005998:Glycine / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009132:Muscles / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011487:Protein Conformation; D021122:Protein Subunits / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D018009:Receptors, Glycine / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013654:Taurine / Q000494:pharmacology
D018722:Nicotinic Agonists; D021122:Protein Subunits; D000644:Quaternary Ammonium Compounds; D018009:Receptors, Glycine; D011978:Receptors, Nicotinic; D013654:Taurine; C027917:tetramethylammonium; D005998:Glycine