AUTHOR=Gutorov Rita , Peters Maximilian , Katz Ben , Brandwine Tal , Barbera Nicolas A. , Levitan Irena , Minke Baruch 

TITLE=Modulation of Transient Receptor Potential C Channel Activity by Cholesterol

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 10 - 2019

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.01487

DOI=10.3389/fphar.2019.01487

ISSN=1663-9812

ABSTRACT=Many studies have shown the involvement of cholesterol in the modulation of ion channels function. The mechanisms suggested for these effects included a highly flexible binding site, adopting multiple poses in a “cloud”, rather than occupying a single conformation, or the perturbation of specific lipid environments. Previous observations have suggested reversible targeting of mammalian Transient Receptor Potential C (TRPC) channels to cholesterol-rich membrane environment of lipid rafts. This led to the suggestion that the inhibitory effects of cholesterol depletion by methyl-β-cyclodextrin (MβCD) on mammalian TRPC channel activity may result mainly from disruption of lipid raft architecture, including impaired local assembly of signaling molecules into multimolecular signaling complexes, rather than disruption of a direct gating process. The Drosophila TRP and TRP-Like (TRPL) channels belong to the TRPC channel subfamily. When Drosophila S2 or HEK cells heterologously expressing TRPL were perfused with MβCD, the TRPL-dependent current was rapidly abolished in less than 100s, which fits well with the fast kinetic phase of cholesterol sequestration experiments in cells. Assuming an analogy between channel modulation by cholesterol sequestration of TRPL and other TRPC channels, we suggest that the fast kinetics of TRPL channel suppression by MβCD arise from disruption of lipid rafts. Accordingly, suppression of TRPC channel activity by cholesterol sequestration via disruption of lipid rafts may give us a clue as to the still unknown gating mechanism of these channels.