On the nature of partial agonism in the nicotinic receptor superfamily

Abstract

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. Partial agonists have a place in pharmacology and clinical applications too, where a modest response is required. They bind to and activate a receptor, but elicit a smaller response than a true or full agonist. For those that act on ligand-activated ion channels it has been assumed for 50 years that they are simply inefficient at inducing the conformational change that opens and shuts the channel. A study of two partial agonists for nicotinic acid receptors — taurine and tetramethylammonium — shows that once bound to the receptor, they are as effective at opening the channel as a full agonist. Rather, 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 for the design of partial agonists for therapeutic use. Ligand-gated ion channels can be opened by both full and partial agonists, though in the case of a partial agonist, the maximum response is only a fraction of that evoked by a full agonist. The mechanism underlying this pharmacological observation is investigated and it is shown that cys-loop receptors bound to partial agonists are as efficient at opening as those that are bound to full agonists. Instead, the diminished response results from a reduced ability to adopt an intermediate (agonist bound but pre-open) state.