Inflammatory pain regulation through TRPV1 ion channel and phosphoinositide signaling

Abstract

Inflammatory pain is one of the biggest challenges facing contemporary society. The TRPV1 ion channel is a major player in inflammatory pain. During inflammation TRPV1 is regulated by both modulation of gating and changes in channel number on the plasma membrane. Phosphoinositides are a class of membrane lipids which are directly involved in regulation of channel activity and signaling. PIP2 is a phosphoinositide which affects gating of TRPV1 but whether it activates or inhibits was controversial. We showed that under physiological conditions PIP2 activates TRPV1, while in non-physiological conditions, PIP2 inhibits TRPV1, which resolves the controversy in the literature. The phospholipid PIP3 is a product of a lipid kinase called PI3K, which is also involved in inflammatory pain. During inflammation, increased PI3K activity leads to increased PIP3, which leads to fusion of vesicles containing TRPV1 with the plasma membrane. This mechanism underlies increased sensitivity to pain during inflammation. We identified a novel mechanism for reciprocal regulation between PI3K and TRPV1 during inflammation, which results in potentiation of PI3K activity. A soluble fragment of TRPV1 called the ARD was sufficient to reproduce this effect. To move this work further, we are optimizing a novel opto-PI3K system to achieve better spatial and temporal control of PI3K activity. This will be significant for advancing our understanding of the mechanism of inflammatory pain and opening possibilities for developing new treatments.