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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).

References associated with 8.A.64 family:

Gao, X.F., J.F. Feng, W. Wang, Z.H. Xiang, X.J. Liu, C. Zhu, Z.X. Tang, X.Z. Dong, and C. He. (2015). Pirt reduces bladder overactivity by inhibiting purinergic receptor P2X3. Nat Commun 6: 7650. 26151598
Hilton, J.K., T. Salehpour, N.J. Sisco, P. Rath, and W.D. Van Horn. (2018). Phosphoinositide-interacting regulator of TRP (PIRT) has opposing effects on human and mouse TRPM8 ion channels. J. Biol. Chem. [Epub: Ahead of Print] 29724821
Sisco, N.J., C.V.M. Helsell, and W.D. Van Horn. (2019). Competitive Interactions between PIRT, the Cold Sensing Ion Channel TRPM8, and PIP Suggest a Mechanism for Regulation. Sci Rep 9: 14128. 31575973
Sisco, N.J., D.D. Luu, M. Kim, and W.D. Van Horn. (2020). PIRT the TRP Channel Regulating Protein Binds Calmodulin and Cholesterol-Like Ligands. Biomolecules 10:. 32245175
Tang M., Wu GY., Dong XZ. and Tang ZX. (2016). Phosphoinositide interacting regulator of TRP (Pirt) enhances TRPM8 channel activity in vitro via increasing channel conductance. Acta Pharmacol Sin. 37(1):98-104. 26657057