PIRT (phosphoinositide interacting regulator of transient receptor potential channels) is a two-transmembrane regulatory protein that modulates multiple TRP ion channels through phosphoinositide binding and protein-protein interactions. PIRT primarily functions as a positive regulator of TRPV1, a noxious heat and capsaicin sensor, by enhancing channel activity via phosphatidylinositol 4,5-bisphosphate (PIP2) 1. For TRPM8 (cold sensor), PIRT exhibits species-dependent effects: mouse PIRT enhances conductance while human PIRT attenuates it, through direct binding to the channel's S1-S4 domain with 1:1 stoichiometry 2. PIRT also inhibits P2X3 purinergic receptors via its N-terminal 14 amino acids, reducing bladder overactivity in mice 3. Beyond TRP channels, PIRT binds calmodulin and cholesterol-like ligands, expanding its regulatory scope 1. PIRT is predominantly expressed in peripheral sensory neurons, particularly nociceptors, where it modulates pain and temperature sensation 4. Functionally, PIRT regulates TRPM8-mediated cold sensing through competitive PIP2 interactions, forming regulatory complexes that control local lipid accessibility 5. In females, PIRT deficiency causes subtle metabolic alterations including increased obesity susceptibility on low-fat diets 6. These findings establish PIRT as a critical integrator of sensory signaling with implications for pain, thermoregulation, and metabolic homeostasis.