Affinage

PIRT

Phosphoinositide-interacting protein · UniProt P0C851

Length
137 aa
Mass
15.3 kDa
Annotated
2026-06-10
20 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIRT is a two-transmembrane membrane protein of peripheral sensory neurons that functions as a regulatory subunit for multiple temperature- and ligand-gated ion channels, integrating phosphoinositide signaling with channel activity to shape somatosensation (PMID:18455988, PMID:23863968). It binds the TRPV1 C-terminal cytoplasmic domain together with PIP2 through a cluster of basic residues in its own C-terminus, and is a necessary component for PIP2-dependent potentiation of TRPV1 currents (PMID:18455988). PIRT is likewise an endogenous positive regulator of the cold/menthol receptor TRPM8, binding directly to the channel's S1–S4 transmembrane domain at roughly 1:1 stoichiometry and acting synergistically with PIP2 to raise single-channel conductance; PIRT and the TRPM8 S1–S4 domain compete for PIP2, so PIRT modulates the channel by controlling local PIP2 availability, with species-specific directionality (mouse PIRT enhances mouse TRPM8 while human PIRT attenuates human TRPM8, an effect mapping to the channel pore) (PMID:23863968, PMID:26657057, PMID:29724821, PMID:31575973). Beyond TRP channels, PIRT uses its N-terminal 14 residues to bind and inhibit the purinergic receptor P2X3, and a TAT-conjugated N14 peptide is sufficient to suppress P2X3 activation and relieve bladder overactivity (PMID:26151598). PIRT also binds calmodulin through its C-terminal α-helix and cholesterol-derivatives through a CRAC motif in its first transmembrane helix (PMID:32245175). Functionally, PIRT is required across itch signaling pathways and contributes to neuropathic pain in the same pathway as TRPV1 (PMID:21655234, PMID:29808083).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2008 High

    Established PIRT's foundational role: it was unknown how PIP2 regulation was coupled to TRPV1, and this work showed PIRT is a dedicated regulatory subunit whose C-terminus bridges TRPV1 and phosphoinositides.

    Evidence C-terminus pulldown with TRPV1 and phosphoinositides, basic-residue mutagenesis, heterologous electrophysiology, and Pirt-null DRG recordings

    PMID:18455988

    Open questions at the time
    • No structure of the PIRT-TRPV1 complex
    • Stoichiometry of PIRT within the TRPV1 complex not defined
    • Whether the same basic cluster mediates other channel interactions not addressed
  2. 2011 Medium

    Extended PIRT function beyond TRPV1 by showing it is required for both TRPV1-dependent and TRPV1-independent itch, indicating PIRT participates in multiple sensory signaling pathways.

    Evidence Pirt-/- mouse behavioral assays with multiple pruritogens and DRG calcium imaging

    PMID:21655234

    Open questions at the time
    • No molecular partner identified for the TRPV1-independent itch pathway
    • Mechanism linking PIRT loss to reduced itch undefined
  3. 2013 High

    Answered whether PIRT regulates cold sensation: Pirt loss blunts cold behavior and PIRT raises TRPM8 menthol/cold sensitivity, identifying PIRT as an endogenous positive TRPM8 regulator.

    Evidence Pirt knockout cold-behavior assays and TRPM8+Pirt heterologous electrophysiology

    PMID:23863968

    Open questions at the time
    • Binding site on TRPM8 not yet mapped
    • Whether PIP2 is involved not addressed in this study
  4. 2015 High

    Defined a distinct inhibitory mode: PIRT's N-terminal 14 residues directly bind and inhibit P2X3, and the isolated peptide is therapeutically sufficient, showing PIRT is not exclusively a potentiator and acts via discrete domains on different channels.

    Evidence Co-IP, N-terminal deletion mapping, heterologous electrophysiology, and TAT-N14 peptide rescue in Pirt-/- mice

    PMID:26151598

    Open questions at the time
    • Structural basis of N14-P2X3 contact unknown
    • Whether N14 inhibition generalizes to other P2X subtypes not tested
  5. 2015 Medium

    Resolved the biophysical mechanism of TRPM8 potentiation: PIRT and PIP2 act synergistically and PIRT increases single-channel conductance rather than open probability.

    Evidence Whole-cell and cell-attached single-channel recordings with intracellular PIP2 application

    PMID:26657057

    Open questions at the time
    • Single lab, not independently replicated
    • Structural explanation for conductance change absent
  6. 2016 Low

    Suggested PIRT regulation extends to enteric purinergic signaling by showing co-localization and co-IP with P2X2 in the gut.

    Evidence Immunofluorescence co-localization and co-immunoprecipitation in mouse enteric nervous system

    PMID:27105971

    Open questions at the time
    • Co-IP and co-localization without functional electrophysiological validation
    • No directionality of effect on P2X2 established
    • Binding interface unmapped
  7. 2018 High

    Mapped the PIRT-TRPM8 physical interaction and uncovered species divergence: PIRT binds the TRPM8 S1–S4 domain ~1:1, but human PIRT attenuates while mouse PIRT enhances, an effect localized to the channel pore.

    Evidence NMR binding with purified TRPM8 S1–S4 and full-length human PIRT, pulldown, chimeric-channel electrophysiology, and trafficking Westerns

    PMID:29724821

    Open questions at the time
    • No atomic-resolution complex structure
    • Mechanism by which pore residues dictate directionality unresolved
  8. 2018 Medium

    Placed PIRT in the same pathway as TRPV1 for neuropathic pain via genetic/pharmacological epistasis, with combined loss exceeding single perturbation.

    Evidence Pirt-/- CCI model behavior, DRG calcium imaging, and Pirt KO combined with TRPV1 block

    PMID:29808083

    Open questions at the time
    • Molecular events downstream of PIRT in neuropathic sensitization undefined
    • Single lab
  9. 2019 Medium

    Provided the unifying competitive-PIP2 model: PIRT and the TRPM8 S1–S4 domain compete for PIP2, so PIRT modulates TRPM8 by regulating local PIP2 availability.

    Evidence Solution NMR backbone assignment of full-length human PIRT, MST binding, and computational PIP2 docking

    PMID:31575973

    Open questions at the time
    • Competition shown biochemically but not in a native membrane channel complex
    • Single lab
  10. 2020 Medium

    Broadened the PIRT interactome to lipid- and calcium-signaling ligands, identifying calmodulin binding via the C-terminal helix and cholesterol-derivative binding via a CRAC motif in TM1.

    Evidence MST, pulldown, NMR-detected binding, and Rosetta computational modeling

    PMID:32245175

    Open questions at the time
    • No functional consequence demonstrated for calmodulin or cholesterol binding
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PIRT integrates its multiple physical inputs (PIP2, calmodulin, cholesterol) into channel-specific potentiation versus inhibition, and the structural basis of each channel complex, remains unresolved.
  • No high-resolution structure of any PIRT-channel complex
  • Functional role of calmodulin and cholesterol binding undefined
  • Mechanism switching PIRT between potentiator and inhibitor unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 2
Partners
CALM1P2X2P2X3TRPM8TRPV1
Complex memberships
PIRT-TRPM8-PIP2 complexPIRT-TRPV1-PIP2 complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 PIRT functions as a regulatory subunit of TRPV1: its C-terminus directly binds TRPV1 and multiple phosphoinositides including PIP2 (binding dependent on a cluster of basic residues), and heterologous expression of PIRT strongly enhances TRPV1-mediated currents. PIP2 potentiation of TRPV1 requires PIRT, placing PIRT as a necessary component of the TRPV1 complex for PIP2-dependent channel regulation. Co-immunoprecipitation / direct binding assay (C-terminus pulldown with TRPV1 and phosphoinositides), heterologous expression in HEK cells with whole-cell electrophysiology, Pirt null mouse DRG recordings, mutagenesis of basic residues in C-terminus Cell High 18455988
2013 PIRT functions as an endogenous positive regulator of TRPM8: Pirt-/- mice show decreased behavioral responses to cold, and PIRT increases TRPM8 sensitivity to menthol and cool temperatures in heterologous expression systems. Pirt knockout mouse behavioral assays (cold plate, acetone evaporation), heterologous expression electrophysiology in HEK cells co-transfected with TRPM8 and Pirt Nature communications High 23863968
2015 PIRT inhibits P2X3 receptor activity through a direct interaction mediated by the N-terminal 14 amino-acid residues of PIRT. PIRT co-localizes with P2X3 in bladder nerve fibers, and a TAT-conjugated Pirt N14 peptide is sufficient to inhibit P2X3 activation in bladder DRG neurons and alleviate bladder overactivity in Pirt-/- mice. Co-immunoprecipitation (Pirt-P2X3), heterologous expression electrophysiology, N-terminal peptide deletion mapping, TAT-peptide rescue experiments in Pirt-/- mice, immunofluorescence co-localization Nature communications High 26151598
2015 PIRT and PIP2 synergistically enhance TRPM8 channel activity, and the mechanism involves PIRT increasing single-channel conductance (not open probability). Intracellular PIP2 (but not PI) enhances TRPM8 currents, and PIRT co-expression potentiates this effect synergistically. Whole-cell patch-clamp electrophysiology in HEK293 cells co-transfected with TRPM8±Pirt, cell-attached single-channel recordings in CHO cells, intracellular PIP2 application via pipette Acta pharmacologica Sinica Medium 26657057
2018 Human PIRT has opposing effects on human TRPM8 compared to mouse PIRT on mouse TRPM8: human PIRT attenuates human TRPM8 conductance whereas mouse PIRT enhances mouse TRPM8. This species difference maps to the TRPM8 pore domain as shown with chimeric channels. PIRT binds directly and specifically to the TRPM8 S1-S4 transmembrane domain with ~1:1 stoichiometry (four PIRT-binding sites per tetrameric channel). Comparative electrophysiology in heterologous cells, chimeric TRPM8 channel constructs, Western blot for membrane trafficking, NMR binding experiments with purified TRPM8 S1-S4 domain and full-length human PIRT, pulldown assay The Journal of biological chemistry High 29724821
2019 PIRT, TRPM8, and PIP2 form a regulatory complex in which PIRT and the TRPM8 S1-S4 domain compete for PIP2 binding. NMR backbone assignment of full-length human PIRT and microscale thermophoresis (MST) binding studies identified competitive interactions between PIRT-PIP2 and PIRT-TRPM8 S1-S4, suggesting PIRT modulates TRPM8 by regulating local PIP2 availability. Solution NMR spectroscopy (backbone resonance assignment of full-length human PIRT), microscale thermophoresis (MST) binding assays, computational PIP2 docking to TRPM8 comparative model Scientific reports Medium 31575973
2020 PIRT binds calmodulin through its C-terminal α-helix, and also binds cholesterol-derivatives through a cholesterol-recognition amino acid consensus (CRAC) domain in the outer leaflet of its first transmembrane helix. PIRT additionally binds cholecalciferol and oxytocin. Microscale thermophoresis (MST) binding assays, pulldown experiment, NMR-detected binding study, Rosetta-based computational studies Biomolecules Medium 32245175
2011 PIRT is required for both histamine-dependent and histamine-independent itch signaling, including forms of itch that are both TRPV1-dependent and TRPV1-independent, extending PIRT function beyond TRPV1 regulation to multiple itch signaling pathways. Pirt-/- mouse behavioral assays with multiple pruritogens, DRG neuron calcium imaging PloS one Medium 21655234
2016 PIRT co-localizes with P2X2 receptors in the mouse enteric nervous system (myenteric and submucosal plexuses), and co-immunoprecipitation shows PIRT co-precipitates with P2X2, suggesting PIRT may regulate P2X2 receptor function in the gut. Immunofluorescence co-localization, co-immunoprecipitation Purinergic signalling Low 27105971
2018 PIRT together with TRPV1 is involved in CCI-induced neuropathic pain: Pirt-/- mice show attenuated mechanical allodynia and thermal hyperalgesia in CCI models, and the combined dysfunction of both Pirt and TRPV1 produces greater pain attenuation than either alone, indicating Pirt acts in the same pathway as TRPV1 in neuropathic pain. Pirt-/- mouse CCI model behavioral assays, DRG neuron calcium imaging, immunofluorescence, real-time PCR, genetic epistasis (double KO/pharmacology) Neural plasticity Medium 29808083

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Pirt, a phosphoinositide-binding protein, functions as a regulatory subunit of TRPV1. Cell 178 18455988
2020 Mapping of Sensory Nerve Subsets within the Vagal Ganglia and the Brainstem Using Reporter Mice for Pirt, TRPV1, 5-HT3, and Tac1 Expression. eNeuro 69 32060036
2013 Pirt functions as an endogenous regulator of TRPM8. Nature communications 46 23863968
2011 Pirt, a TRPV1 modulator, is required for histamine-dependent and -independent itch. PloS one 46 21655234
2022 scRNA-sequencing reveals subtype-specific transcriptomic perturbations in DRG neurons of Pirt mice in neuropathic pain condition. eLife 44 36264609
2018 Pirt Together with TRPV1 Is Involved in the Regulation of Neuropathic Pain. Neural plasticity 27 29808083
2015 Pirt reduces bladder overactivity by inhibiting purinergic receptor P2X3. Nature communications 20 26151598
2015 Pirt contributes to uterine contraction-induced pain in mice. Molecular pain 18 26376721
2018 Phosphoinositide-interacting regulator of TRP (PIRT) has opposing effects on human and mouse TRPM8 ion channels. The Journal of biological chemistry 12 29724821
2023 piRT-IFC: Physics-informed real-time impedance flow cytometry for the characterization of cellular intrinsic electrical properties. Microsystems & nanoengineering 10 37303829
2021 Ca2+ Signalling Induced by NGF Identifies a Subset of Capsaicin-Excitable Neurons Displaying Enhanced Chemo-Nociception in Dorsal Root Ganglion Explants from Adult pirt-GCaMP3 Mouse. International journal of molecular sciences 10 33806699
2015 Phosphoinositide interacting regulator of TRP (Pirt) enhances TRPM8 channel activity in vitro via increasing channel conductance. Acta pharmacologica Sinica 10 26657057
2016 Co-localization of Pirt protein and P2X2 receptors in the mouse enteric nervous system. Purinergic signalling 9 27105971
2021 [Involvement of Pirt /TRPV1 signaling in acupuncture-induced reduction of visceral hypersensitivity in diarrhea-predominant irritable bowel syndrome rats]. Zhen ci yan jiu = Acupuncture research 8 33931991
2019 Competitive Interactions between PIRT, the Cold Sensing Ion Channel TRPM8, and PIP2 Suggest a Mechanism for Regulation. Scientific reports 8 31575973
2021 Population Coding of Capsaicin Concentration by Sensory Neurons Revealed Using Ca2+ Imaging of Dorsal Root Ganglia Explants from Adult pirt-GCaMP3 Mouse. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 5 34242501
2020 PIRT the TRP Channel Regulating Protein Binds Calmodulin and Cholesterol-Like Ligands. Biomolecules 5 32245175
2019 Pirt deficiency has subtle female-specific effects on energy and glucose metabolism in mice. Molecular metabolism 4 30902502
2025 PIRT-Seq: a high-resolution whole-genome assay to identify protein-coding genes. Nucleic acids research 1 40808296
2025 In vivo Pirt-Marina voltage sensor imaging detects primary sensory neuron-specific voltage dynamics and neuronal plasticity changes. Proceedings of the National Academy of Sciences of the United States of America 1 40938705

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