| First Author | Nayak TK | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 49 | Pages | 17660-5 |
| PubMed ID | 25422413 | Mgi Jnum | J:216725 |
| Mgi Id | MGI:5609453 | Doi | 10.1073/pnas.1414378111 |
| Citation | Nayak TK, et al. (2014) Functional differences between neurotransmitter binding sites of muscle acetylcholine receptors. Proc Natl Acad Sci U S A 111(49):17660-5 |
| abstractText | A muscle acetylcholine receptor (AChR) has two neurotransmitter binding sites located in the extracellular domain, at alphadelta and either alphaepsilon (adult) or alphagamma (fetal) subunit interfaces. We used single-channel electrophysiology to measure the effects of mutations of five conserved aromatic residues at each site with regard to their contribution to the difference in free energy of agonist binding to active versus resting receptors (DeltaGB1). The two binding sites behave independently in both adult and fetal AChRs. For four different agonists, including ACh and choline, DeltaGB1 is approximately -2 kcal/mol more favorable at alphagamma compared with at alphaepsilon and alphadelta. Only three of the aromatics contribute significantly to DeltaGB1 at the adult sites (alphaY190, alphaY198, and alphaW149), but all five do so at alphagamma (as well as alphaY93 and gammaW55). gammaW55 makes a particularly large contribution only at alphagamma that is coupled energetically to those contributions of some of the alpha-subunit aromatics. The hydroxyl and benzene groups of loop C residues alphaY190 and alphaY198 behave similarly with regard to DeltaGB1 at all three kinds of site. ACh binding energies estimated from molecular dynamics simulations are consistent with experimental values from electrophysiology and suggest that the alphagamma site is more compact, better organized, and less dynamic than alphaepsilon and alphadelta. We speculate that the different sensitivities of the fetal alphagamma site versus the adult alphaepsilon and alphadelta sites to choline and ACh are important for the proper maturation and function of the neuromuscular synapse. |
