Chronic Alteration in Phosphatidylinositol 4,5-Biphosphate Levels Regulates Capsaicin and Mustard Oil Responses

There is an agreement that acute (in minutes) hydrolysis and accumulation of phosphatidylinositol 4,5-bisphosphate (PIP2) modulate TRPV1 and TRPA1 activities. Because inflammation results in PIP2 depletion, persisting for long periods (hours to days) in pain models and in the clinic, we examined whether chronic depletion and accumulation of PIP2 affect capsaicin (CAP) and mustard oil (MO) responses. In addition, we wanted to evaluate whether the effects of PIP2 depend on TRPV1 and TRPA1 coexpression and whether the PIP2 actions vary in expression cells vs. sensory neurons. Chronic PIP2 production was stimulated by overexpression of phosphatidylinositol-4-phosphate-5-kinase, and PIP2-specific phospholipid 5'-phosphatase was selected to reduce plasma membrane levels of PIP2. Our results demonstrate that CAP (100 nM) responses and receptor tachyphylaxis are not significantly influenced by chronic changes in PIP2 levels in wild-type (WT) or TRPA1 null-mutant sensory neurons as well as CHO cells expressing TRPV1 alone or with TRPA1. However, low concentrations of CAP (20 nM) produced a higher response after PIP2 depletion in cells containing TRPV1 alone but not TRPV1 together with TRPA1. MO (25 mu M) responses were also not affected by PIP2 in WT sensory neurons and cells coexpressing TRPA1 and TRPV1. In contrast, PIP2 reduction leads to pronounced tachyphylaxis to MO in cells with both channels. Chronic effect of PIP2 on TRPA1 activity depends on presence of the TRPV1 channel and cell type (CHO vs. sensory neurons). In summary, chronic alterations in PIP2 levels regulate magnitude of CAP and MO responses as well as MO tachyphylaxis. This regulation depends on coexpression profile of TRPA1 and TRPV1 and cell type. (C) 2011 Wiley-Liss, Inc.