Boundary Lipids In The Nicotinic Acetylcholine Receptor Microenvironment

Abstract

The structural and functional properties of the nicotinic acetylcholine receptor (AChR), the archetype molecule in the superfamily of Cys-looped ligand-gated ion channels, are strongly dependent on the lipids in the vicinal microenvironment. The influence on receptor properties is mainly exerted by the AChR-vicinal ("shell" or "annular") lipids, which occur in the liquid-ordered phase as opposed to the more disordered and "fluid" bulk membrane lipids. Fluorescence studies from our laboratory have identified discrete sites for fatty acids, phospholipids, and cholesterol on the AChR protein, and electron-spin resonance spectroscopy has enabled the establishment of the stoichiometry and selectivity of the shell lipid for the AChR and the disclosure of lipid sites in the AChR transmembrane region. Experimental evidence supports the notion that the interface between the protein moiety and the adjacent lipid shell is the locus of a variety of pharmacologically relevant processes, including the action of steroids and other lipids. I surmise that the outermost ring of M4 helices constitutes the boundary interface, most suitable to convey the signals from the lipid microenvironment to the rest of the transmembrane region, and to the channel inner ring in particular.

Lipid Rafts Control P2X3 Receptor Distribution and Function in Trigeminal Sensory Neurons of a Transgenic Migraine Mouse Model

“…Likewise, lipid microenvironment in form of "shell" or "annular" lipids has a strong effect on the structural and functional properties of the nicotinic receptors [49-51] as cholesterol is an absolute requirement for their stability, supramolecular organization and function [52-54]. …”

Cellular and Molecular Targets of Menthol Actions

“…In previous investigations, it was demonstrated that even slight changes in adjacent lipid structure can cause important alterations in the function of LGICs by changing the energetics of conformational transitions in the protein structure (Fantini and Barrantes, 2009; Barrantes et al, 2010). Besides their interaction with membranes, menthol and other monoterpenes can bind directly to residues of the transmembrane domains and alter the functional properties of LGICs.…”

NMR structure of the transmembrane domain of the n-acetylcholine receptor β2 subunit

“…But the interaction of TM2 with the rest of the transmembrane domain is not trivial. Both mutations in the lipid-facing TM4 helix [26-33] and changes in lipid environment [20, 34] have been shown to affect ion channel assembly and function. The role of TM4 in stabilizing the transmembrane domain is supported by the observation that pentameric assembly of homologous receptors truncated after TM3 were rescued in oocytes by coexpressing the complementary TM4 helix, even though TM4 does not directly form a subunit interface [33].…”