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:

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.
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]
Liu, Y., Y. Wang, Y. Lou, W. Tian, and K. Que. (2021). Functional expression of TRPA1 channel, TRPV1 channel and TMEM100 in human odontoblasts. J Mol Histol. [Epub: Ahead of Print]
Pan, C., Y. Jiao, D. Kong, H. Deng, S. Xu, D. Tang, W. Yin, P. Gao, W. Yu, Y. Fan, and D. Wen. (2022). Upregulation of DRG protein TMEM100 facilitates dry-skin-induced pruritus by enhancing TRPA1 channel function. Acta Biochim Biophys Sin (Shanghai) 55: 1-13.
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.
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:.
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.
Examples:

TC#NameOrganismal TypeExample
8.A.64.1.1

PIRT (phosphoinositide-interacting protein) of 137 aas and 2 TMSs.  Regulates Trp-CC channels (TC# 1.A.4) (Tang et al. 2015) including TRPM8 (Hilton et al. 2018).  PIRT also regulates 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 various ion channels (Sisco et al. 2020).

PIRT of Homo sapiens

 
8.A.64.1.2

TMEM100 or PIRT of 134 aas and 2 TMSs.

PIRT of Takifugu rubripes (Japanese pufferfish) (Fugu rubripes)

 
8.A.64.1.3

Uncharacterized protein of 339 aas and 2 TMSs.

UP of Helobdella robusta (Californian leech)

 
8.A.64.1.4

Uncharacterized protein of 292 aas and 2 TMSs

UP of Branchiostoma floridae (Florida lancelet) (Amphioxus)

 
8.A.64.1.5

Uncharacterized protein of 161 aas and 2 TMSs.

UP of Capitella teleta (Polychaete worm)

 
8.A.64.1.6

Uncharacteerized protein of 331 aas and 2 TMSs.

UP of Piriformospora indica

 
8.A.64.1.7

Pirt of 147 aas and 2 TMSs.

Pirt of Xenopus tropicalis (Western clawed frog) (Silurana tropicalis)

 
8.A.64.1.8

Transmembrane protein 100, TMEM100 of 134 aas and 2 TMSs. It plays a role during embryonic arterial endothelium differentiation and vascular morphogenesis through the ACVRL1 receptor-dependent signaling pathway upon stimulation by bone morphogenetic proteins, such as GDF2/BMP9 and BMP10. It is also involved in the regulation of nociception, acting as a modulator of the interaction between TRPA1 and TRPV1, two molecular sensors and mediators of pain signals in dorsal root ganglia (DRG) neurons. Mechanistically, it weakens their interaction, thereby releasing the inhibition of TRPA1 by TRPV1 and increasing the single-channel open probability of the TRPA1-TRPV1 complex. It is expressed together with these two TRP channel proteins in odontoblasts (Liu et al. 2021). Upregulation of the DRG protein, TMEM100, facilitates dry-skin-induced pruritus by enhancing TRPA1 channel function (Pan et al. 2022).

TMEM100 of Homo sapiens