TY - JOUR
T1 - Pirt, a Phosphoinositide-Binding Protein, Functions as a Regulatory Subunit of TRPV1
AU - Kim, Andrew Y.
AU - Tang, Zongxiang
AU - Liu, Qin
AU - Patel, Kush N.
AU - Maag, David
AU - Geng, Yixun
AU - Dong, Xinzhong
N1 - Funding Information:
We thank Drs. M. Caterina for TRPV1 stable HEK293 cells, TRPV1, and TRPM8 cDNAs; P. Worley for GluR1-HA cDNA and pCMV-GST construct; N. Tigue for hTRPA1 stable HEK293 cells. We also thank Drs. M. Caterina, M. Chung, and A. Kolodkin for helpful comments on the manuscript. The cloning of Pirt and initial in situ hybridization using Pirt cRNA were carried out in the laboratory of Dr. D. Anderson (California Institute of Technology). The liposomal pulldown experiment was performed in the laboratory of Dr. S.H. Snyder (Johns Hopkins University). X.D. is supported by an NINDS grant (NS054791).
PY - 2008/5/2
Y1 - 2008/5/2
N2 - 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.
AB - 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.
KW - MOLNEURO
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U2 - 10.1016/j.cell.2008.02.053
DO - 10.1016/j.cell.2008.02.053
M3 - Article
C2 - 18455988
AN - SCOPUS:42949125051
SN - 0092-8674
VL - 133
SP - 475
EP - 485
JO - Cell
JF - Cell
IS - 3
ER -