Nanoscale interactions between the nicotinic acetylcholine receptor and cholesterol
Laboratory of Molecular Neurobiology, Institute of Biomedical Research (BIOMED) UCA-CONICET, Faculty of Medical Sciences, Buenos Aires, Argentina
* Address correspondence to: Francisco J. Barrantes,
# This is a solicited review summarizing the plenary lecture presented at the joint international meeting of the Pan-American Association for Biochemistry and Molecular Biology and the Argentine Society for Biochemical and Molecular Biology Investigations (SAIB) in Salta, Argentina
Received 12 March 2021; Accepted 29 April 2021 ; Published online 17 June 2021
Cholesterol is a major lipid in biological membranes. It not only plays a structural role but also modulates a wide range of functional properties of neurotransmitter and hormone receptors and ion channels. The membraneembedded segments of the paradigm neurotransmitter receptor for acetylcholine (nAChR) contain linear sequences of amino acids with the capacity to recognize cholesterol. These cholesterol consensus domains have been designated as “CARC” and its mirror sequence “CRAC”. CARC preferentially occurs in the exoplasmic-facing membrane leaflet, and CRAC, in the cytoplasmic-facing hemilayer. Both motifs are highly conserved among ion-channel and neurotransmitter receptor proteins in vertebrate nervous systems, where they recognize cholesterol, and in prokaryotic homologues in bacteria, where they recognize hopanoids. This phylogenetically conserved trait is an indication that the hopanoids in some bacteria and cholesterol in eukaryotes subserve analogous functions, probably contributing to the stability of membrane-embedded protein domains. Structural studies from our laboratory using superresolution optical microscopy (“nanoscopy”) have disclosed other interrelated functional and structural properties exerted by cholesterol on the nAChR. The neutral lipid content at the cell surface influences both the macromolecular organization of the receptor and its translational mobility (diffusion) in the plane of the membrane.
Cholesterol, Pentameric ligand-gated ion channel, Nicotinic acetylcholine receptor, Membrane proteins, Evolution, Nanoscopy, Cholesterol-recognition domains