Phosphoinositide Regulation of TRP Channels: A Functional Overview in the Structural Era

Abstract

Transient receptor potential (TRP) ion channels have diverse activation mechanisms including physical stimuli, such as high or low temperatures, and a variety of intracellular signaling molecules. Regulation by phosphoinositides and their derivatives is their only known common regulatory feature. For most TRP channels, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂] serves as a cofactor required for activity. Such dependence on PI(4,5)P₂ has been demonstrated for members of the TRPM subfamily and for the epithelial TRPV5 and TRPV6 channels. Intracellular TRPML channels show specific activation by PI(3,5)P₂. Structural studies uncovered the PI(4,5)P₂ and PI(3,5)P₂ binding sites for these channels and shed light on the mechanism of channel opening. PI(4,5)P₂ regulation of TRPV1-4 as well as some TRPC channels is more complex, involving both positive and negative effects. This review discusses the functional roles of phosphoinositides in TRP channel regulation and molecular insights gained from recent cryo-electron microscopy structures.

Keywords: PIP2; TRP channels; TRPM3; TRPM8; TRPV1; phosphoinositides.