N-glycosylation at the conserved sites ensures the expression of properly folded functional ACh receptors

Brain Res Mol Brain Res. 1997 May;45(2):219-29. doi: 10.1016/s0169-328x(96)00256-2.

Abstract

The role of the conserved carbohydrate moiety in the expression of complete acetylcholine receptor (AChR), alpha2 beta gamma delta was re-investigated by expressing additional site-directed mutant subunits, lacking an N-glycosylation site, in Xenopus oocytes. All mutant subunits were stably expressed and appeared to associate with other normal subunits; however, removal of carbohydrate on the alpha subunit inhibited the formation of 125I-alpha-bungarotoxin (alpha-BuTX) binding sites and functional ACh-gated ion channels. 125I-alpha-BuTX binding to AChRs was also significantly reduced by removal of the conserved carbohydrate on the gamma or delta subunits. Immunoprecipitation with monoclonal antibodies that recognize the two distinct alpha-BuTX sites on the AChR indicated that the mutant gamma subunit did not interfere with efficient formation of the alpha-BuTX binding site at the alpha/delta interface, but loss of the carbohydrate did interfere with formation of the alpha-BuTX binding site at the alpha/mutant gamma interface. A similar result was obtained with the mutant delta subunit. Furthermore, the mutant gamma and mutant delta subunits were not incorporated efficiently into the mature (correct tertiary conformation capable of alpha-BuTX binding) alpha beta delta or alpha beta gamma complexes, respectively. Since both mutant gamma and mutant delta subunits were capable of assembling with the alpha subunits (immature assembly), these results suggest that the formation of the two alpha-BuTX binding sites requires correct folding of the alpha gamma and alpha delta complexes, which is aided by the conserved carbohydrate on the gamma and delta subunits. Electrophysiological experiments demonstrated that functional receptors containing mutant subunits were produced, but the functional properties of the mutant receptors were differentially altered, depending on the subunit mutated. Together, our results suggest that N-glycosylation of AChR subunits ensures the correct folding of important functional domains and expression of proper functional receptors in the plasma membrane.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / pharmacology
  • Amino Acid Sequence
  • Animals
  • Asparagine
  • Aspartic Acid
  • Binding Sites
  • Bungarotoxins / metabolism
  • Cloning, Molecular
  • Conserved Sequence
  • Female
  • Glycosylation
  • Ion Channels / chemistry
  • Ion Channels / physiology
  • Kinetics
  • Macromolecular Substances
  • Membrane Potentials / drug effects
  • Oocytes / physiology
  • Patch-Clamp Techniques
  • Point Mutation
  • Protein Folding*
  • RNA, Messenger / metabolism
  • Receptors, Cholinergic / biosynthesis
  • Receptors, Cholinergic / chemistry*
  • Receptors, Cholinergic / physiology*
  • Xenopus laevis

Substances

  • Bungarotoxins
  • Ion Channels
  • Macromolecular Substances
  • RNA, Messenger
  • Receptors, Cholinergic
  • Aspartic Acid
  • Asparagine
  • Acetylcholine