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Elife. 2018 Dec 18;7. pii: e38869. doi: 10.7554/eLife.38869.

Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor.

Author information

1
Department of Physiology and Biophysics, University of Washington, Seattle, United States.
2
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
3
Department of Pediatrics and Graduate Program in Neuroscience, University of Washington, Seattle, United States.

Abstract

Although it has been known for over a decade that the inflammatory mediator NGF sensitizes pain-receptor neurons through increased trafficking of TRPV1 channels to the plasma membrane, the mechanism by which this occurs remains mysterious. NGF activates phosphoinositide 3-kinase (PI3K), the enzyme that generates PI(3,4)P2 and PIP3, and PI3K activity is required for sensitization. One tantalizing hint came from the finding that the N-terminal region of TRPV1 interacts directly with PI3K. Using two-color total internal reflection fluorescence microscopy, we show that TRPV1 potentiates NGF-induced PI3K activity. A soluble TRPV1 fragment corresponding to the N-terminal Ankyrin repeats domain (ARD) was sufficient to produce this potentiation, indicating that allosteric regulation was involved. Further, other TRPV channels with conserved ARDs also potentiated NGF-induced PI3K activity. Our data demonstrate a novel reciprocal regulation of PI3K signaling by the ARD of TRPV channels.

KEYWORDS:

NGF; PI3K; PIP3; TRPV1; TRPV2; biochemistry; chemical biology; inflammation; molecular biophysics; none; structural biology

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