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Effect of cholesterol depletion on the pore dilation of TRPV1

Erik T. Jansson (Institutionen för kemi- och bioteknik, Fysikalisk kemi) ; Carolina L. Trkulja (Institutionen för kemi- och bioteknik, Fysikalisk kemi) ; Aikeremu Ahemaiti (Institutionen för kemi- och bioteknik, Fysikalisk kemi) ; Maria Millingen (Institutionen för kemi- och bioteknik, Fysikalisk kemi) ; Gavin Jeffries (Institutionen för kemi- och bioteknik, Fysikalisk kemi) ; Kent Jardemark (Institutionen för kemi- och bioteknik, Fysikalisk kemi) ; Owe Orwar (Institutionen för kemi- och bioteknik, Fysikalisk kemi)
Molecular Pain (1744-8069). Vol. 9 (2013), 1,
[Artikel, refereegranskad vetenskaplig]

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.

Nyckelord: TRPV1, Cholesterol, MβCD, Capsaicin, Acidic pH, YO-PRO, Ion-permeability, NMDG



Denna post skapades 2013-02-05. Senast ändrad 2016-07-19.
CPL Pubid: 172979

 

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Institutioner (Chalmers)

Institutionen för kemi- och bioteknik, Fysikalisk kemi (2005-2014)

Ämnesområden

Fysikalisk kemi

Chalmers infrastruktur

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