Importance of the membrane in ligand-receptor interactions

NMR data that underscore the importance of the membrane in ligand-receptor interactions were obtained and analyzed. The following hypothesis for acetylcholine (ACh) binding to the acetylcholine receptor (AChR) is proposed: ACh first binds to the membrane, where it adopts its bioactive conformation, and it then rapidly diffuses along the membrane to bind to the AChR in its already-correct conformation. Data used to support this hypothesis include (a) the NMR-determined binding constant of KM = (2.8 +/- 0.6) x 10(3) M-1 for the binding of ACh to the asolectin membrane, (b) the lipid dependence of AChR activity, (c) the location of the ACh binding site close to the membrane surface, and (d) the conformation of ACh in its membrane-bound state. Additional experiments to test this hypothesis are proposed.