Phosphoinositide regulation of TRPV1 revisited

Abstract

The heat- and capsaicin-sensitive Transient Receptor Potential Vanilloid 1 ion channel (TRPV1) is regulated by plasma membrane phosphoinositides. The effects of these lipids on this channel have been controversial. Recent articles re-ignited the debate and also offered resolution to place some of the data in a coherent picture. This review summarizes the literature on this topic and provides a detailed and critical discussion on the experimental evidence for the various effects of phosphatidylinositol 4,5-bisphosphayte [PI(4,5)P2 or PIP2] on TRPV1. We conclude that PI(4,5)P2 and potentially its precursor PI(4)P are positive cofactors for TRPV1, acting via direct interaction with the channel, and their depletion by Ca2+-induced activation of phospholipase Cδ isoforms (PLCδ) limits channel activity during capsaicin-induced desensitization. Other negatively charged lipids at higher concentrations can also support channel activity, which may explain some controversies in the literature. PI(4,5)P2 also partially inhibits channel activity in some experimental settings, and relief from this inhibition upon PLCβ activation may contribute to sensitization. The negative effect of PI(4,5)P2 is more controversial and its mechanism is less well understood. Other TRP channels from the TRPV and TRPC families may also undergo similar dual regulation by phosphoinositides, thus the complexity of TRPV1 regulation is not unique to this channel.

Endogenous TRPV1 stimulation leads to the activation of the inositol phospholipid pathway necessary for sustained Ca2+ oscillations

“…It is known that TRPV1 channels are modulated by phospholipids such as PIP2 [20,21], but our results revealed that the activation of endogenous TRPV1 leads to the production of inositol trisphosphate, thereby reducing the levels of PIP2 in the plasma membrane creating a negative feedback loop.…”

“…3E). When cells were pre-treated with 50 μM U-73122, CAPS treatment didn't induce oscillations, only single Ca 2+ transients were observed in 14-22% of cells (Fig 3F) Activation of phospholipase C results in consider that both activation and inhibition of phospholipase C has an effect on the phospholipid composition of the plasma membrane that subsequently influences the sensitivity of TRPV1 channels [20,21]. The importance of InsP 3 in the generation of Ca 2+ oscillations was further verified by overexpression of the InsP 3 -metabolizing enzyme InsP 3 -5 phosphatase.…”

Phosphoinositide signaling in somatosensory neurons

“…Depletion of PI(4,5)P 2 and relief from inhibition by this lipid has been also proposed to play a role in acute sensitization (Chuang et al, 2001; Cao et al, 2013), but this effect is probably auxiliary to PKC (Lukacs et al, 2013b), and somewhat controversial. As we have recently reviewed this topic in detail (Rohacs, 2015), its detailed discussion is beyond the scope of this review.…”

“…These channels undergo desensitization during prolonged exposure to capsaicin. Several different Ca 2+ dependent mechanisms, such as calmodulin (Numazaki et al, 2003; Rosenbaum et al, 2004; Lishko et al, 2007) and calcineurin (Docherty et al, 1996; Mohapatra and Nau, 2005) have been proposed to play a role in desensitization, but depletion of PI(4,5)P 2 and PI(4)P by Ca 2+ -induced PLC activation is emerging as a key mechanism (Liu et al, 2005; Lishko et al, 2007; Lukacs et al, 2007; Lukacs et al, 2013b) reviewed in (Rohacs, 2015). …”

Sensing mechanisms and individuality of heat stress in mammalian cells

“…Moreover purified PLC δ which binds to PI(4,5)P2 inhibits the channel activity causing a feedback inhibition (Rohacs 2015). Nevertheless, in the intact cells there is a dual effect; in the presence of high concentrations of capsaicin PIP2 activates TRPV1 channel ,in the low capsaicin or moderate heat treatment increased PIP2 levels inhibited the channel activity whereas a moderate PIP2 depletion activated (Lukacs et al 2007).…”