| TRPV1 is a nonselective cation channel of six putative transmembrane domains, first identified by its responsiveness to capsaicin from hot chili peppers. TRPV1 can also be activated by acid (pH <6) and noxious heat (>43°C). In the mouse, TRPV1 is expressed primarily in small-to-medium diameter peptidergic sensory neurons, characteristic of nociceptive AS- and C-fibers and is implicated in pain sensation. Despite the clear physiological importance of TRPV1 channel, little is known about the associated proteins or subunit structures of TRPV1. We identified a novel membrane protein called Pin (Phosphoinositide interacting regulator of TR1, from a screen designed to isolate nociceptive genes. Pirt is expressed in most nociceptive neurons in the dorsal root ganglia (DRG) including TRPV1-positive cells. Pirt null mice show impaired responsiveness to noxious heat and capsaicin. Noxious heat- and capsaicin-sensitive currents in Pirt-deficient DRG neurons are significantly attenuated. Heterologous expression of Pirt strongly enhances TRPV1-mediated currents. Furthermore, the C-terminus of Pirt binds to TRPV1 and several phosphoinositides, including phosphatidylinositol-4,5-bisphosphate (PIP2), and can potentiate TRPV1. The PIP2 binding is dependent on the cluster of basic residues in the Pin C-terminus and is crucial for Pirt regulation of TRPV1. Importantly, the enhancement of TRPV1 by PIP2 requires Pirt. Therefore, Pirt is a key component of the TRPV1 complex and positively regulates TRPV1 activity. |
