A-kinase anchoring protein 79/150 scaffolds transient receptor potential a 1 phosphorylation and sensitization by metabotropic glutamate receptor activation

Allison Doyle Brackley, Ruben Gomez, Kristi A. Guerrero, Armen N. Akopian, Marc J. Glucksman, Junhui Du, Susan M. Carlton, Nathaniel A. Jeske

Research output: Research - peer-reviewArticle

Abstract

Mechanical pain serves as a base clinical symptom for many of the world's most debilitating syndromes. Ion channels expressed by peripheral sensory neurons largely contribute to mechanical hypersensitivity. Transient Receptor Potential A 1 (TRPA1) is a ligand-gated ion channel that contributes to inflammatory mechanical hypersensitivity, yet little is known as to the post-translational mechanism behind its somatosensitization. Here, we utilize biochemical, electrophysiological, and behavioral measures to demonstrate that metabotropic glutamate receptor-induced sensitization of TRPA1 nociceptors stimulates targeted modification of the receptor. Type 1 mGluR5 activation increases TRPA1 receptor agonist sensitivity in an AKA-dependent manner. As a scaffolding protein for Protein Kinases A and C (PKA and PKC, respectively), AKAP facilitates phosphorylation and sensitization of TRPA1 in ex vivo sensory neuronal preparations. Furthermore, hyperalgesic priming of mechanical hypersensitivity requires both TRPA1 and AKAP. Collectively, these results identify a novel AKAP-mediated biochemical mechanism that increases TRPA1 sensitivity in peripheral sensory neurons, and likely contributes to persistent mechanical hypersensitivity.

LanguageEnglish (US)
Article number1842
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Metabotropic Glutamate Receptors
Protein Kinases
Hypersensitivity
Phosphorylation
Sensory Receptor Cells
Ligand-Gated Ion Channels
Nociceptors
Cyclic AMP-Dependent Protein Kinases
Ion Channels
Protein Kinase C
Pain
Proteins

ASJC Scopus subject areas

  • General

Cite this

A-kinase anchoring protein 79/150 scaffolds transient receptor potential a 1 phosphorylation and sensitization by metabotropic glutamate receptor activation. / Brackley, Allison Doyle; Gomez, Ruben; Guerrero, Kristi A.; Akopian, Armen N.; Glucksman, Marc J.; Du, Junhui; Carlton, Susan M.; Jeske, Nathaniel A.

In: Scientific Reports, Vol. 7, No. 1, 1842, 01.12.2017.

Research output: Research - peer-reviewArticle

Brackley, Allison Doyle ; Gomez, Ruben ; Guerrero, Kristi A. ; Akopian, Armen N. ; Glucksman, Marc J. ; Du, Junhui ; Carlton, Susan M. ; Jeske, Nathaniel A./ A-kinase anchoring protein 79/150 scaffolds transient receptor potential a 1 phosphorylation and sensitization by metabotropic glutamate receptor activation. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
@article{cfeba5641e8346e98b9b07b4244923db,
title = "A-kinase anchoring protein 79/150 scaffolds transient receptor potential a 1 phosphorylation and sensitization by metabotropic glutamate receptor activation",
abstract = "Mechanical pain serves as a base clinical symptom for many of the world's most debilitating syndromes. Ion channels expressed by peripheral sensory neurons largely contribute to mechanical hypersensitivity. Transient Receptor Potential A 1 (TRPA1) is a ligand-gated ion channel that contributes to inflammatory mechanical hypersensitivity, yet little is known as to the post-translational mechanism behind its somatosensitization. Here, we utilize biochemical, electrophysiological, and behavioral measures to demonstrate that metabotropic glutamate receptor-induced sensitization of TRPA1 nociceptors stimulates targeted modification of the receptor. Type 1 mGluR5 activation increases TRPA1 receptor agonist sensitivity in an AKA-dependent manner. As a scaffolding protein for Protein Kinases A and C (PKA and PKC, respectively), AKAP facilitates phosphorylation and sensitization of TRPA1 in ex vivo sensory neuronal preparations. Furthermore, hyperalgesic priming of mechanical hypersensitivity requires both TRPA1 and AKAP. Collectively, these results identify a novel AKAP-mediated biochemical mechanism that increases TRPA1 sensitivity in peripheral sensory neurons, and likely contributes to persistent mechanical hypersensitivity.",
author = "Brackley, {Allison Doyle} and Ruben Gomez and Guerrero, {Kristi A.} and Akopian, {Armen N.} and Glucksman, {Marc J.} and Junhui Du and Carlton, {Susan M.} and Jeske, {Nathaniel A.}",
year = "2017",
month = "12",
doi = "10.1038/s41598-017-01999-4",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - A-kinase anchoring protein 79/150 scaffolds transient receptor potential a 1 phosphorylation and sensitization by metabotropic glutamate receptor activation

AU - Brackley,Allison Doyle

AU - Gomez,Ruben

AU - Guerrero,Kristi A.

AU - Akopian,Armen N.

AU - Glucksman,Marc J.

AU - Du,Junhui

AU - Carlton,Susan M.

AU - Jeske,Nathaniel A.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Mechanical pain serves as a base clinical symptom for many of the world's most debilitating syndromes. Ion channels expressed by peripheral sensory neurons largely contribute to mechanical hypersensitivity. Transient Receptor Potential A 1 (TRPA1) is a ligand-gated ion channel that contributes to inflammatory mechanical hypersensitivity, yet little is known as to the post-translational mechanism behind its somatosensitization. Here, we utilize biochemical, electrophysiological, and behavioral measures to demonstrate that metabotropic glutamate receptor-induced sensitization of TRPA1 nociceptors stimulates targeted modification of the receptor. Type 1 mGluR5 activation increases TRPA1 receptor agonist sensitivity in an AKA-dependent manner. As a scaffolding protein for Protein Kinases A and C (PKA and PKC, respectively), AKAP facilitates phosphorylation and sensitization of TRPA1 in ex vivo sensory neuronal preparations. Furthermore, hyperalgesic priming of mechanical hypersensitivity requires both TRPA1 and AKAP. Collectively, these results identify a novel AKAP-mediated biochemical mechanism that increases TRPA1 sensitivity in peripheral sensory neurons, and likely contributes to persistent mechanical hypersensitivity.

AB - Mechanical pain serves as a base clinical symptom for many of the world's most debilitating syndromes. Ion channels expressed by peripheral sensory neurons largely contribute to mechanical hypersensitivity. Transient Receptor Potential A 1 (TRPA1) is a ligand-gated ion channel that contributes to inflammatory mechanical hypersensitivity, yet little is known as to the post-translational mechanism behind its somatosensitization. Here, we utilize biochemical, electrophysiological, and behavioral measures to demonstrate that metabotropic glutamate receptor-induced sensitization of TRPA1 nociceptors stimulates targeted modification of the receptor. Type 1 mGluR5 activation increases TRPA1 receptor agonist sensitivity in an AKA-dependent manner. As a scaffolding protein for Protein Kinases A and C (PKA and PKC, respectively), AKAP facilitates phosphorylation and sensitization of TRPA1 in ex vivo sensory neuronal preparations. Furthermore, hyperalgesic priming of mechanical hypersensitivity requires both TRPA1 and AKAP. Collectively, these results identify a novel AKAP-mediated biochemical mechanism that increases TRPA1 sensitivity in peripheral sensory neurons, and likely contributes to persistent mechanical hypersensitivity.

UR - http://www.scopus.com/inward/record.url?scp=85019175105&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019175105&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-01999-4

DO - 10.1038/s41598-017-01999-4

M3 - Article

VL - 7

JO - Scientific Reports

T2 - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 1842

ER -