Effect of Cholesterol on the Pore Dilation of TRPV1

Abstract

The transient receptor potential vanilloid 1 (TRPV1) ion channel is expressed in nociceptors, where pharmacological modulation of its function may offer a way of easing pain and neurogenic inflammation processes in the human body. The aim of this study was to investigate how depletion of cholesterol from the cell membrane may modulate ion-permeability of the TRPV1 ion channel expressed in CHO-cells. The ion-permeability properties of TRPV1 measured with whole-cell patch clamp on a Chinese hamster ovary (CHO) cell line expressing TRPV1. Sustained capsaicin-induced activation of TRPV1 with N-methyl-D-glucamine (NMDG) as the sole external cation, generated a biphasic current, with a first outward current and a second inward current. Similarly, sustained proton-activation (pH 5.5) of TRPV1 in the absence of external calcium also generated a biphasic current, with a first fast current peak followed by a second larger one. Also, patch clamp recordings of reversal potentials revealed a change of the ion-permeability during prolonged activation of the TRPV1 channel in extremely low extracellular calcium. Our findings show that depletion of cholesterol from the cell membrane inhibited both the second current resulting from sustained agonist-activation, and the change in ion-permeability of the TRPV1 channel. Our results propose a novel mechanism by which cholesterol-depletion may modulate the ion channel function of TRPV1, which may constitute a novel pharmacological based approach for the treatment of pain and neurogenic pain.