Direct Interactions of Cholesterol With Pentameric Ligand-Gated Ion Channels: Testable Hypotheses From Computational...

Several essential ionotropic neurotransmitter receptors, including the nicotinic acetylcholine receptor (nAChR) and gamma-aminobutyric acid (GABA) type A receptor (GABA_Ar), belong to the family of pentameric ligand-gated ion channels (pLGICs). Function of these receptors is particularly sensitive to their lipid environment, including cholesterol and cholesterol-derived neurosteroids. Direct structural data investigating interactions between sterols and pLGICs, as well as their role in modulatory mechanisms, are largely unavailable. Physics-based computational approaches can serve a vital role in interpretation of more indirect data as well as hypothesis generation and experimental design. In this chapter, I report several examples in which computational approaches were used to predict direct binding interactions of steroids and pLGICs, evaluate the relative likelihood of possible interpretations of experimental data, and present rationally designed simple experiments. I conclude by offering several predictions that could be tested by future experiments.