Cholesterol exerts different modulatory effects at the cell surface of muscle and neuronal nicotinic acetylcholine receptors

Abstract

Communication at synapses requires the location and maintenanceof receptors at specific sites. Factors controlling the distribution ofreceptors are critical determinants of the cell response to externalsignals. The nicotinic acetylcholine receptor (AChR) is the bestcharacterized ligand-gated ion channel, found at neuromuscularjunctions and central nervous system synapses. We have reportedthat cholesterol contributes to the homeostasis of muscle-typereceptor levels at the plasmalemma (Kumari et al., J. Cell Biol.,2008; Borroni and Barrantes, J. Biol. Chem., 2011). Cyclodextrin-mediated acute cholesterol depletion lowered the number of cell-surface muscle AChRs in CHO-K1/A5 cells and C2C12 musclecells. In contrast, the same treatment, performed on culturedhippocampal neurons, increased the amount ofa7 AChR at theplasmalemma. In addition, chronic cholesterol reduction mediatedby Mevinolin, an inhibitor of cholesterol biosynthesis, augmentedthe cell-surface levels ofa7 AChR anda4b2 neuronal AChRsubtypes measured by fluorescence microscopy and radioactiveligand binding assays. The results suggest that cholesterol modu-lates surface AChR levels differentially in peripheral and centralcholinergic synapses