Thiel_2022_Int.J.Mol.Sci_23_

Transient receptor potential (TRP) channels are cation channels that play a regulatory role in pain and thermosensation, insulin secretion, and neurotransmission. It has been proposed that activation of TRP channels requires phosphatidylinositol 4,5-bisphosphate, the major substrate for phospholipase C (PLC). We investigated whether inhibition of PLCbeta has an impact on TRP channel signaling. A genetic approach was used to avoid off-target effects observed when using a pharmacological PLCbeta inhibitor. In this study, we show that expression of PLCbeta1ct and PLCbeta3ct, truncated forms of PLCbeta1 or PLCbeta3 that contain the C-terminal membrane binding domains, almost completely blocked the signal transduction of a Galphaq-coupled designer receptor, including the phosphorylation of ERK1/2. In contrast, expression of the helix-turn-helix motif (Halpha1-Halpha2) of the proximal C-terminal domain of PLCbeta3 did not affect Galphaq-coupled receptor signaling. PLCbeta3ct expression impaired signaling of the TRP channels TRPM3 and TRPM8, stimulated with either prognenolone sulfate or icilin. Thus, the C-terminal domain of PLCbeta3 interacts with plasma membrane targets, most likely phosphatidylinositol 4,5-bisphosphate, and in this way blocks the biological activation of TRPM3 and TRPM8, which require interaction with this phospholipid. PLCbeta thus regulates TRPM3 and TRPM8 channels by masking phosphatidylinositol 4,5-bisphosphate with its C-terminal domain.