Ceramides modulate cell-surface acetylcholine receptor levels

Abstract

The effects of ceramides (Cer) on the trafficking of the nicotinic acetylcholine receptor (AChR) to the plasma membrane were studied in CHO-K1/A5 cells, a clonal cell line that heterologously expresses the adult murine form of the receptor. When cells were incubated with short- (C6-Cer) or long- (brain-Cer) chain Cer at low concentrations, an increase in the number of cell-surface AChRs was observed concomitant with a decrease in intracellular receptor levels. The alteration in AChR distribution by low Cer treatment does not appear to be a general mechanism since the surface expression of the green fluorescent protein derivative of the vesicular stomatitis virus protein (VSVG-GFP) was not affected. High Cer concentrations caused the opposite effects, decreasing the number of cell-surface AChRs, which exhibited higher affinity for [125I]-alpha-bungarotoxin, and increasing the intracellular pool, which colocalized with trans-Golgi/TGN specific markers. The generation of endogenous Cer by sphingomyelinase treatment also decreased cell-surface AChR levels. These effects do not involve protein kinase C zeta or protein phosphatase 2A activation. Taken together, the results indicate that Cer modulate trafficking of AChRs to and stability at the cell surface.

Nicotinic acetylcholine receptor–lipid interactions: Mechanistic insight and biological function

“…Lipid rafts/microdomains are typically enriched in cholesterol, which orders and increases the hydrophobic thickness of the bilayer [57,135]. Both muscle-type and neuronal nAChRs require lipid rafts for trafficking to the plasma membrane, with the raft-forming lipids cholesterol, sphingolipids, and ceramides being important [107,108,[136][137][138]. Disruption of these rafts leads to both altered cell surface exposure and altered nAChR function [138,139].…”

Blockade of Lysosomal Acid Ceramidase Induces GluN2B-Dependent Tau Phosphorylation in Rat Hippocampal Slices

“…For instance, ceramide production has been proposed to be involved CD40, CD95, and Fc-gamma receptor clustering [25–27]. Consistent with their potential participation in the regulation of neurotransmitter systems, initial reports examining the role of ceramides in the control of acetylcholine receptors indicated that these sphingolipids are possibly involved in controlling cell-surface expression of both nicotinic [10, 28, 29] and muscarinic [30] subtypes of receptors [10, 28, 29]. The present study, in conjunction with previous findings [12], indicates that enzymatically accumulated ceramides also interact with mechanisms capable of favoring the upregulation of NMDA-mediated responses.…”

“…Ceramides have recently been implicated in membrane-trafficking events involved in the maintenance of muscarinic [10] and glutamatergic [11] receptors at the membrane surface. In particular, Wheeler et al [12] established that enhanced ceramide levels increase the number of NMDA subtypes of ionotropic glutamate receptors in lipid rafts of hippocampal synapses.…”

C2-ceramide inhibits the prostaglandin E2-induced accumulation of cAMP in human gingival fibroblasts

“…Decreases in cholesterol or sphingolipid levels have been demonstrated to induce changes in the distribution of nicotinic acetylcholine receptors, diminishing the number of surface receptors (2,5,13). Recently, ceramides have been demonstrated to modulate cell-surface nicotinic acetylcholine receptor levels in CHO-K1/A5 cells, a Chinese hamster ovary clonal cell line (10). Therefore, it is likely that ceramides regulate PGE 2 receptor levels via Open columns, cAMP-elevating agents; solid columns, C 2 -ceramide-treated and then cAMPelevating agents.…”