Regulation of transient receptor potential channels by the phospholipase C pathway

Abstract

Transient Receptor Potential (TRP) channels were discovered while analyzing visual mutants in Drosophila. The protein encoded by the transient receptor potential (trp) gene is a Ca(2+) permeable cation channel activated downstream of the phospholipase C (PLC) pathway. While searching for homologs in other organisms, a surprisingly large number of mammalian TRP channels was cloned. The regulation of TRP channels is quite diverse, but many of them are either activated downstream of PLC, or modulated by it. This review will summarize the current knowledge on regulation of TRP channels by PLC, with special focus on TRPC-s, which can be considered as effectors of PLC and the heat- and capsaicin-sensitive TRPV1, which is modulated by the PLC pathway in a complex manner.

Figure 1

Potential activation mechanisms of mammalian TRPC and drosophila visual TRP channels. The cartoon is a compilation of activation mechanisms proposed on a variety of channels in this family; note that there is not one specific channel where all of these mechanisms have been demonstrated.

Figure 2

Sensitization and desensitization of TRPV1. A. Top, Graphical summary of changes in phosphoinositide levels during sensitization in DRG neurons, based on data from (Lukacs, 2013). Briefly, upon GPCR stimulation by Bradykinin, PLCβ activation leads to a moderate decrease in PI(4,5)P₂, but no change in PI(4)P. The decrease in PI(4,5)P₂ levels synergizes with PKC activation to potentiate TRPV1 activity. Bottom, Representative trace for sensitization of TRPV1 in a DRG neuron in the whole-cell configuration: the cell was stimulated with 100 nM capsaicin, then 500 nM bradykinin was applied, then the cell was stimulated by 100 nM capsaicin again. B. Top, Upon maximal TRPV1 activation, Ca²⁺-induced PLCδ activation leads to a robust decrease in PI(4,5)P₂ and PI(4)P. Even though PKC is likely to be activated, its effect is over-ridden by the robust decrease in phosphoinostide levels and thus channel activity decreases. Bottom, Representative trace for desensitization in a DRG neuron in the perforated patch configuration: two subsequent stimulations by a saturating concentration of capsaicin (1 μM). Traces are modified from (Lukacs, 2013), scale bars are 100 pA and 1 min for both traces.

Figure 3

Model for Ca²⁺-dependent desensitization/inactivation of TRP channels. Calcium influx though various TRP channels activate a Ca²⁺ selective PLC, likely PLCδ isoform, that leads to depletion of PI(4,5)P₂, and in some cases [PI(4)P], leading to diminished channel activity. This mechanism has been implicated so far in the regulation of TRPM8, TRPV1, TRPV2, and TRPV6, see text for further details.