Abstract
Changes of cholesterol level in the plasma membrane of cells have been shown to modulate ion channel function. The proposed mechanisms underlying these modulations include association of cholesterol to a single binding site at a single channel conformation, association to a highly flexible cholesterol binding site adopting multiple poses, and perturbation of lipid rafts. These perturbations have been shown to induce reversible targeting of mammalian transient receptor potential C (TRPC) channels to the cholesterol-rich membrane environment of lipid rafts. Thus, the observed inhibition of TRPC channels by methyl-β-cyclodextrin (MβCD), which induces cholesterol efflux from the plasma membrane, may result from disruption of lipid rafts. This perturbation was also shown to disrupt multimolecular signaling complexes containing TRPC channels. The Drosophila TRP and TRP-like (TRPL) channels belong to the TRPC channel subfamily. When the Drosophila TRPL channel was expressed in S2 or HEK293 cells and perfused with MβCD, the TRPL current was abolished in less than 100 s, fitting well the fast kinetic phase of cholesterol sequestration experiments in cells. It was thus suggested that the fast kinetics of TRPL channel suppression by MβCD arise from disruption of lipid rafts. Accordingly, lipid raft perturbation by cholesterol sequestration could give clues to the function of lipid environment in TRPC channel activity and its mechanism.
Highlights
Cholesterol molecules are intercalated among the phospholipids of cell membrane forming an integral part of the plasma membrane, which is essential for the proper function of ion channels
We focus on modulations of transient receptor potential C (TRPC) channels activity following application MβCD, with emphasis on fast modulations
Cholesterol was first depleted by means of MβCD in S2 cells expressing TRPL; the excess of MβCD was washed out, and the cells were perfused with the TRPL channel activator linoleic acid (LA). This protocol initially resulted, as expected, in reduction of TRPL currents, but surprisingly, LA could activate the TRPL channels independent of MβCD. These results suggest that in S2 cells, MβCD does not affects the TRPL channels directly but affected G-protein coupled related signaling proteins upstream of TRPL in the cascade
Summary
Rita Gutorov 1, Maximilian Peters 1, Ben Katz 1, Tal Brandwine 1, Nicolas A. The proposed mechanisms underlying these modulations include association of cholesterol to a single binding site at a single channel conformation, association to a highly flexible cholesterol binding site adopting multiple poses, and perturbation of lipid rafts. These perturbations have been shown to induce reversible targeting of mammalian transient receptor potential C (TRPC) channels to the cholesterolrich membrane environment of lipid rafts. The observed inhibition of TRPC channels by methyl-β-cyclodextrin (MβCD), which induces cholesterol efflux from the plasma membrane, may result from disruption of lipid rafts.
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