The energetic consequences of loop 9 gating motions in acetylcholine receptor-channels

J Physiol. 2012 Jan 1;590(1):119-29. doi: 10.1113/jphysiol.2011.213892. Epub 2011 Oct 24.

Abstract

Acetylcholine receptor-channels (AChRs) mediate fast synaptic transmission between nerve and muscle. In order to better-understand the mechanism by which this protein assembles and isomerizes between closed- and open-channel conformations we measured changes in the diliganded gating equilibrium constant (E(2)) consequent to mutations of residues at the C-terminus of loop 9 (L9) in the α and ε subunits of mouse neuromuscular AChRs. These amino acids are close to two interesting interfaces, between the extracellular and transmembrane domain within a subunit (E–T interface) and between primary and complementary subunits (P–C interface). Most α subunit mutations modestly decreased E(2) (mainly by slowing the channel-opening rate constant) and sometimes produced AChRs that had heterogeneous gating kinetic properties. Mutations in the ε subunit had a larger effect and could either increase or decrease E(2), but did not induce kinetic heterogeneity. There are broad-but-weak energetic interactions between αL9 residues and others at the αE–T interface, as well as between the εL9 residue and others at the P–C interface (in particular, the M2–M3 linker). These interactions serve, in part, to maintain the structural integrity of the AChR assembly at the E–T interface. Overall, the energy changes of L9 residues are significant but smaller than in other regions of the protein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylcholine / genetics*
  • Acetylcholine / metabolism*
  • Animals
  • Binding Sites
  • Cell Line, Transformed
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Cell Membrane / physiology
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / genetics*
  • Ion Channel Gating / physiology*
  • Kinetics
  • Mice
  • Molecular Conformation
  • Muscles / metabolism
  • Muscles / physiology
  • Point Mutation
  • Protein Structure, Tertiary
  • Protein Subunits
  • Receptors, Cholinergic / genetics*
  • Receptors, Cholinergic / metabolism*

Substances

  • Protein Subunits
  • Receptors, Cholinergic
  • Acetylcholine