Phospholipase C Mediated Modulation of TRPV1 Channels

Abstract

The Transient Receptor Potential Vanilloid type 1 (TRPV1) channels are involved in both thermosensation and nociception. They are activated by heat, protons and capsaicin, and modulated by a plethora of other agents. This review will focus on the consequences of phospholipase C (PLC) activation, with special emphasis on the effects of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) on these channels. Two opposing effects of PIP 2 have been reported on TRPV1. PIP 2 has been proposed to inhibit TRPV1, and relief from this inhibition was suggested to be involved in sensitization of these channels by pro-inflammatory agents. In excised patches, however, PIP 2 was shown to activate TRPV1. Calcium flowing through TRPV1 activates PLC and the resulting depletion of PIP 2 was proposed to play a role in capsaicin-induced desensitization of these channels. We will describe the data indicating involvement of PLC and PIP 2 in sensitization and desensitization of TRPV1, and will also discuss other pathways potentially contributing to these two phenomena. We attempt to resolve the seemingly contradictory data by proposing that PIP 2 can both activate and inhibit TRPV1 depending on the experimental conditions, more specifically on the level of stimulation of these channels. Finally, we also discuss data in the literature indicating that other TRP channels, TRPA1 and some members of the TRPC subfamily, may also be under a similar dual control by PIP 2 .

Calcium signals induced by FGF-2 in parasympathetic neurons: Role of second messenger pathways

“…Among the TRP channels that have been shown to be activated/modulated by PIP 2 are several TRPMs [12,20], TRPC6 [10], TRPV5 [11]. TRPV1, one of the best characterized members of the superfamily, has been shown to be both activated and inactivated by PIP 2 , depending on the experimental conditions [19]. Finally, Saleh [21] have shown a complex mechanism of activation of TRPC1 channels by PIP 2 and PIP 3 , the product of the PI3K-mediated phosphorilation of PIP 2 .…”

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

“…**TrpV1 channels also called vanilloid receptors that respond to heat and capsaicin (224) are strongly sensitized by bradykinin and other PLC activators, and it was suggested that PtdIns(4,5)P 2 breakdown relieves a tonic inhibition of these channels by PtdIns(4,5)P 2 (257). However, the lipid regulation of these channels appears to be more complicated as they need phosphoinositides for their activity, and the effects of PtdIns(4,5)P 2 also depend on the extent of stimulation by capsaicin (951,1286,1587) or association with other proteins (728,780) and PtdIns4P may also support their activities (559, 951).…”

TRP Channels and Pruritus

“…Indeed, bradykinin [183,184], ATP [185], lipoxygenase products [182,183], prostaglandins [186,187], histamine [188], various neurotrophins (NGF, neurotrophin-3 and -4) [91,102,184], TNF- [189,190], pro-inflammatory chemokines [191], and PAR2 [192,193] were all reported to sensitize TRPV1 via various signal transduction pathways. TRPV1 was shown to be modulated by the protein kinase C (PKC) [183,[194][195][196], phospholipase C (PLC), and phosphatidylinositol 4,5-bisphosphate (PIP 2 ) [184,[197][198][199][200] systems as well as by intracellular ATP [201]. The sensitization process eventually results in the shift of the activation temperature and voltage threshold towards more physiological ranges [195,[202][203][204].…”