Type III Nrg1 back signaling enhances functional TRPV1 along sensory axons contributing to basal and inflammatory thermal pain sensation

Type III Nrg1, a member of the Nrg1 family of signaling proteins, is expressed in sensory neurons, where it can signal in a bi-directional manner via interactions with the ErbB family of receptor tyrosine kinases (ErbB RTKs). Type III Nrg1 signaling as a receptor (Type III Nrg1 back signaling) can a...

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Bibliographic Details
Published in:	PloS one Vol. 6; no. 9; p. e25108
Main Authors:	Canetta, Sarah E, Luca, Edlira, Pertot, Elyse, Role, Lorna W, Talmage, David A
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 20-09-2011 Public Library of Science (PLoS)
Subjects:	1-Phosphatidylinositol 3-kinase Acetylcholine receptors (nicotinic) Animals Axons Axons - metabolism Behavior Biology Capsaicin Capsaicin - toxicity Capsaicin receptors Cell culture Cell surface Cells, Cultured ErbB protein Experiments Hypersensitivity Immunoblotting Inflammation Inflammation - etiology Inflammation - metabolism Inflammation - pathology Ion channels Kinases Laboratory animals Male Medicine Mice Mice, Knockout Nervous system Neuregulin-1 - physiology Neurobiology Neurons Neurosciences Pain Pain - chemically induced Pain - physiopathology Pain perception Patch-Clamp Techniques Proteins Receptors Rodents Schizophrenia Sensation - drug effects Sensory neurons Sensory Receptor Cells - cytology Sensory Receptor Cells - metabolism Sensory System Agents - toxicity Signal Transduction Signaling Thermal stimuli Thermosensing Transient receptor potential proteins TRPV Cation Channels - physiology Tyrosine New York United States > US
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Summary:	Type III Nrg1, a member of the Nrg1 family of signaling proteins, is expressed in sensory neurons, where it can signal in a bi-directional manner via interactions with the ErbB family of receptor tyrosine kinases (ErbB RTKs). Type III Nrg1 signaling as a receptor (Type III Nrg1 back signaling) can acutely activate phosphatidylinositol-3-kinase (PtdIns3K) signaling, as well as regulate levels of α7* nicotinic acetylcholine receptors, along sensory axons. Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in primary sensory neurons that is necessary for the detection of thermal pain and for the development of thermal hypersensitivity to pain under inflammatory conditions. Cell surface expression of TRPV1 can be enhanced by activation of PtdIns3K, making it a potential target for regulation by Type III Nrg1. We now show that Type III Nrg1 signaling in sensory neurons affects functional axonal TRPV1 in a PtdIns3K-dependent manner. Furthermore, mice heterozygous for Type III Nrg1 have specific deficits in their ability to respond to noxious thermal stimuli and to develop capsaicin-induced thermal hypersensitivity to pain. Cumulatively, these results implicate Type III Nrg1 as a novel regulator of TRPV1 and a molecular mediator of nociceptive function.
Bibliography:	Conceived and designed the experiments: SC EL LR DT. Performed the experiments: SC EL EP. Analyzed the data: SC EL EP LR DT. Wrote the paper: SC DT.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0025108