8.A.64 The Phosphoinositide-interacting Protein (PIRT) Family
PIRT is considered to be a regulatory subunit of various transient recptor potential (TRP) channels. For example, TRPV1, a molecular sensor of noxious heat and capsaicin, is positively regulated by PIRT and phosphatidylinositol 4,5-bisphosphate (PIP2) as well as other phosphoinositides, but not phosphatidylinositol (PI). PIRT and PIP2 also synergistically enhance TRPM8 channel activity by increasing the single channel conductance (Tang et al. 2015). TRPM8, PIRT, and PIP2 form a regulatory complex, and PIRT modulation of TRPM8 activity arises, at least in part, by regulating local concentrations of PIP2 accessible to TRPM8 (Sisco et al. 2019). Moreover, PIRT is an endogenous regulator of the ATP-activated P2X3 channel (TC# 1.A.7.1.6) in bladder cells (Gao et al. 2015). Calmodulin binds to the PIRT C-terminal alpha-helix, and a cholesterol-recognition amino acid consensus (CRAC) domain in the outer leaflet of the first transmembrane helix of PIRT binds to a number of cholesterol-derivatives including cholecalciferol and oxytocin, which explains the role of PIRT in regulating a variety of ion channels (Sisco et al. 2020).