Acetylcholine receptor channels activated by a single agonist molecule.
The neuromuscular acetylcholine receptor (AChR) is an allosteric protein that alternatively adopts inactive versus active conformations (R<-->R). The R shape has a higher agonist affinity and ionic conductance than R. To understand how agonists trigger this gating isomerization, we examined single-channel currents from adult mouse muscle AChRs that isomerize normally without agonists but have only a single site able to use agonist binding energy to motivate gating. We estimated the monoliganded gating equilibrium constant E(1) and the energy change associated with the R versus R change in affinity for agonists. AChRs with only one operational binding site gave rise to a single population of currents, indicating that the two transmitter binding sites have approximately the same affinity for the transmitter ACh. The results indicated that E(1) approximately 4.3 x 10(-3) with ACh, and approximately 1.7 x 10(-4) with the partial-agonist choline. From these values and the diliganded gating equilibrium constants, we estimate that the unliganded AChR gating constant is E(0) approximately 6.5 x 10(-7). Gating changes the stability of the ligand-protein complex by approximately 5.2 kcal/mol for ACh and approximately 3.3 kcal/mol for choline.
Jha
Archana
A
Department of Physiology and Biophysics, State University of New York, Buffalo, New York, USA.
Auerbach
Anthony
A
D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002794:Choline / Q000378:metabolism / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D009154:Mutation; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D018679:Cholinergic Agonists; D007473:Ion Channels; D008024:Ligands; D011950:Receptors, Cholinergic; D002794:Choline; D000109:Acetylcholine