The Energy and Work of a Ligand-Gated Ion Channel

• Published in: Journal of molecular biology 2013-05, Vol.425 (9), p.1461-1475
• Main Author: Auerbach, Anthony
• Format: Article
• Language: English
• Subjects: acetylcholine; acetylcholine receptor; agonists; Allosteric Regulation; Allosteric Regulation - genetics; allostery; Animals; binding sites; Binding Sites - genetics; chemistry; electrophysiology; energy; Energy Metabolism; enthalpy; entropy; gating; genetics; Ion Channel Gating; Ion Channel Gating - genetics; ion channels; isomerization; ligand binding; Ligand-Gated Ion Channels; Ligand-Gated Ion Channels - chemistry; Ligand-Gated Ion Channels - genetics; Ligand-Gated Ion Channels - metabolism; metabolism; Mice; mutation; Receptors, Nicotinic; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - genetics; Receptors, Nicotinic - metabolism; Thermodynamics
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2013.01.027

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=+2.5kcal/mol (−100mV, 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=−5.1kcal/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. [Display omitted] ► Allostery in the AChR can be studied in single molecules with electrophysiology. ► The intrinsic energy changes of the “gating” without ligands are known. ► Most mutations change the intrinsic energy, not that from the ligand. ► The effects of most mutations are additive. ► The ligand energy is from interactions with just three amino acids.