The Energy and Work of a Ligand-Gated Ion Channel Review Article

Ligand-gated ion channels are allosteric membrane proteins that isomerize between C(losed) and O(pen) conformations. A difference in affinity for ligands in the two states influences the C ↔ O “gating” equilibrium constant. The energies associated with adult-type mouse neuromuscular nicotinic acetylcholine receptor (AChR) channel gating have been measured by using single-channel electrophysiology. Without ligands, the free energy, enthalpy and entropy of gating are ΔG0 = + 8.4, ΔH0 = + 10.9 and TΔS0 = + 2.5 kcal/mol (− 100 mV, 23 °C). Many mutations throughout the protein change ΔG0, including natural ones that cause disease. Agonists and most mutations change approximately independently the ground-state energy difference; thus, it is possible to forecast and engineer AChR responses simply by combining perturbations. The free energy of the low ↔ high affinity change for the neurotransmitter at each of two functionally equivalent binding sites is ΔGBACh = − 5.1 kcal/mol. ΔGBACh is set mainly by interactions of ACh with just three binding site aromatic groups. For a series of structurally related agonists, there is a correlation between the energies of low- and high-affinity binding, which implies that gating commences with the formation of the low-affinity complex. Brief, intermediate states in binding and gating have been detected. Several proposals for the nature of the gating transition-state energy landscape and the isomerization mechanism are discussed.