Effect of Cholesterol Depletion on the Pore Dilation of TRPV1

Molecular Pain

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[1] Department of Chemical and Biological Engineering, Chalmers University of Technology, SE-412 96 Göteborg, Sweden;Department of Chemical and Biological Engineering, Chalmers University of Technology, SE-412 96 Göteborg, Sweden;Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;

关键词: TRPV1;    Cholesterol;    MβCD;    Capsaicin;    Acidic pH;    YO-PRO;    Ion-permeability;    NMDG;   

DOI  :  10.1186/1744-8069-9-1

来源: publisher

【 摘 要 】

The TRPV1 ion channel is expressed in nociceptors, where pharmacological modulation of its function may offer a means of alleviating pain and neurogenic inflammation processes in the human body. The aim of this study was to investigate the effects of cholesterol depletion of the cell on ion-permeability of the TRPV1 ion channel. The ion-permeability properties of TRPV1 were assessed using whole-cell patch-clamp and YO-PRO uptake rate studies on a Chinese hamster ovary (CHO) cell line expressing this ion channel. Prolonged capsaicin-induced activation of TRPV1 with N-methyl-D-glucamine (NMDG) as the sole extracellular cation, generated a biphasic current which included an initial outward current followed by an inward current. Similarly, prolonged proton-activation (pH 5.5) of TRPV1 under hypocalcemic conditions also generated a biphasic current including a fast initial current peak followed by a larger second one. Patch-clamp recordings of reversal potentials of TRPV1 revealed an increase of the ion-permeability for NMDG during prolonged activation of this ion channel under hypocalcemic conditions. Our findings show that cholesterol depletion inhibited both the second current, and the increase in ion-permeability of the TRPV1 channel, resulting from sustained agonist-activation with capsaicin and protons (pH 5.5). These results were confirmed with YO-PRO uptake rate studies using laser scanning confocal microscopy, where cholesterol depletion was found to decrease TRPV1 mediated uptake rates of YO-PRO. Hence, these results propose a novel mechanism by which cellular cholesterol depletion modulates the function of TRPV1, which may constitute a novel approach for treatment of neurogenic pain.

【 授权许可】

CC BY