Abstract
Background and Purpose: Agonists turn on receptors because they have
higher affinity for active versus resting conformations of their target
sites. Agonist efficiency (distinct from efficacy) is the fraction of
binding energy applied to the receptor’s activating conformational
change and depends only on the resting/active equilibrium dissociation
constant ratio. Our goal was to estimate agonist efficiency from
concentration-response curves (CRCs). Experimental Approach: Adult
skeletal muscle acetylcholine receptors (AChRs) were expressed in HEK
cells and CRCs were compiled from single-channel currents. The
efficiencies of 13 agonists were estimated from the midpoints and maxima
of the CRCs by using equations that pertain to a cyclic activation
scheme. Key Results: Agonist efficiency was greater for small- compared
to large-volume agonists, 52±2% (n=9) for 70 A3 versus 40±5% (n=4) for
101 A3. The smoking-cessation drugs varenicline and cytisine belong to
the lower efficiency group. An examination of AChRs having a binding
site mutation showed that Y190A was the only one of 22 that affected
the efficiency of ACh, switching it from the more- to the less-efficient
group. IF agonist efficiency is known, EC50 can be estimated from the
maximum response and the unliganded gating equilibrium constant can be
calculated from the CRC parameters. Conclusion and Implications: We
hypothesize that larger agonists have lower efficiencies because they
limit the extent of binding-pocket contraction upon activation, and that
efficiency values may be modal. Knowledge of agonist efficiency
simplifies and extends CRC analysis.