Pirt, a phosphoinositide-binding protein, functions as a regulatory subunit of TRPV1.
Transient receptor potential vanilloid 1 (TRPV1) is a molecular sensor of noxious heat and capsaicin. Its channel activity can be modulated by several mechanisms. Here we identify a membrane protein, Pirt, as a regulator of TRPV1. 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 Pirt 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.
Kim
Andrew Y
AY
The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Tang
Zongxiang
Z
Liu
Qin
Q
Patel
Kush N
KN
Maag
David
D
Geng
Yixun
Y
Dong
Xinzhong
X
D000595:Amino Acid Sequence; D000818:Animals; D002211:Capsaicin / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism; D006358:Hot Temperature; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009475:Neurons, Afferent / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D016415:Sequence Alignment; D050916:TRPV Cation Channels / Q000378:metabolism*
D002352:Carrier Proteins; D008565:Membrane Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; C529003:Pirt protein, mouse; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D002211:Capsaicin