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Science 300 (5623): 1284-1288

Copyright © 2003 by the American Association for the Advancement of Science

A Modular PIP2 Binding Site as a Determinant of Capsaicin Receptor Sensitivity

Elizabeth D. Prescott, and David Julius*

Abstract: The capsaicin receptor (TRPV1), a heat-activated ion channel of the pain pathway, is sensitized by phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis after phospholipase C activation. We identify a site within the C-terminal domain of TRPV1 that is required for PIP2-mediated inhibition of channel gating. Mutations that weaken PIP2-TRPV1 interaction reduce thresholds for chemical or thermal stimuli, whereas TRPV1 channels in which this region is replaced with a lipid-binding domain from PIP2-activated potassium channels remain inhibited by PIP2. The PIP2-interaction domain therefore serves as a critical determinant of thermal threshold and dynamic sensitivity range, tuning TRPV1, and thus the sensory neuron, to appropriately detect heat under normal or pathophysiological conditions.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143–2140, USA.

* To whom correspondence should be addressed. E-mail: julius{at}

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TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons.
N. Hellwig, T. D. Plant, W. Janson, M. Schafer, G. Schultz, and M. Schaefer (2004)
J. Biol. Chem. 279, 34553-34561
   Abstract »    Full Text »    PDF »
Modulation of TRPV1 by nonreceptor tyrosine kinase, c-Src kinase.
X. Jin, N. Morsy, J. Winston, P. J. Pasricha, K. Garrett, and H. I. Akbarali (2004)
Am J Physiol Cell Physiol 287, C558-C563
   Abstract »    Full Text »    PDF »
Regulated Exocytosis Contributes to Protein Kinase C Potentiation of Vanilloid Receptor Activity.
C. Morenilla-Palao, R. Planells-Cases, N. Garcia-Sanz, and A. Ferrer-Montiel (2004)
J. Biol. Chem. 279, 25665-25672
   Abstract »    Full Text »    PDF »
Identification of a Tetramerization Domain in the C Terminus of the Vanilloid Receptor.
N. Garcia-Sanz, A. Fernandez-Carvajal, C. Morenilla-Palao, R. Planells-Cases, E. Fajardo-Sanchez, G. Fernandez-Ballester, and A. Ferrer-Montiel (2004)
J. Neurosci. 24, 5307-5314
   Abstract »    Full Text »    PDF »
Antagonistic Regulation of Native Ca2+- and ATP-sensitive Cation Channels in Brain Capillaries by Nucleotides and Decavanadate.
L. Csanady and V. Adam-Vizi (2004)
J. Gen. Physiol. 123, 743-757
   Abstract »    Full Text »    PDF »
Molecular Determinants of Vanilloid Sensitivity in TRPV1.
N. R. Gavva, L. Klionsky, Y. Qu, L. Shi, R. Tamir, S. Edenson, T. J. Zhang, V. N. Viswanadhan, A. Toth, L. V. Pearce, et al. (2004)
J. Biol. Chem. 279, 20283-20295
   Abstract »    Full Text »    PDF »
Protease-Activated Receptor 2 Sensitizes the Capsaicin Receptor Transient Receptor Potential Vanilloid Receptor 1 to Induce Hyperalgesia.
S. Amadesi, J. Nie, N. Vergnolle, G. S. Cottrell, E. F. Grady, M. Trevisani, C. Manni, P. Geppetti, J. A. McRoberts, H. Ennes, et al. (2004)
J. Neurosci. 24, 4300-4312
   Abstract »    Full Text »    PDF »
BIOCHEMISTRY: Oily Barbarians Breach Ion Channel Gates.
D. W. Hilgemann (2004)
Science 304, 223-224
   Abstract »    Full Text »    PDF »
Nicotine Inhibits Voltage-Dependent Sodium Channels and Sensitizes Vanilloid Receptors.
L. Liu, W. Zhu, Z.-S. Zhang, T. Yang, A. Grant, G. Oxford, and S. A. Simon (2004)
J Neurophysiol 91, 1482-1491
   Abstract »    Full Text »    PDF »
Enhancement of Potency and Efficacy of NADA by PKC-Mediated Phosphorylation of Vanilloid Receptor.
L. S. Premkumar, Z.-H. Qi, J. Van Buren, and M. Raisinghani (2004)
J Neurophysiol 91, 1442-1449
   Abstract »    Full Text »    PDF »
Phosphorylation of Vanilloid Receptor 1 by Ca2+/Calmodulin-dependent Kinase II Regulates Its Vanilloid Binding.
J. Jung, J. S. Shin, S.-Y. Lee, S. W. Hwang, J. Koo, H. Cho, and U. Oh (2004)
J. Biol. Chem. 279, 7048-7054
   Abstract »    Full Text »    PDF »
Design of a High-Affinity Competitive Antagonist of the Vanilloid Receptor Selective for the Calcium Entry-Linked Receptor Population.
A. Toth, P. M. Blumberg, Z. Chen, and A. P. Kozikowski (2004)
Mol. Pharmacol. 65, 282-291
   Abstract »    Full Text »    PDF »

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