A central role for R7bp in the regulation of itch sensation

Mritunjay Pandey, Jian Hua Zhang, Santosh K. Mishra, Poorni R. Adikaram, Benjamin Harris, John F. Kahler, Anna Loshakov, Roxanne Sholevar, Allison Genis, Claire Kittock, Juraj Kabat, Sundar Ganesan, Richard R. Neubig, Mark A. Hoon, William F. Simonds

Research output: Contribution to journalArticle

Abstract

Itch is a protective sensation producing a desire to scratch. Pathologic itch can be a chronic symptom of illnesses such as uremia, cholestatic liver disease, neuropathies and dermatitis, however current therapeutic options are limited. Many types of cell surface receptors, including those present on cells in the skin, on sensory neurons and on neurons in the spinal cord, have been implicated in itch signaling. The role of G protein signaling in the regulation of pruriception is poorly understood. We identify here 2 G protein signaling components whose mutation impairs itch sensation. R7bp (a.k.a. Rgs7bp) is a palmitoylated membrane anchoring protein expressed in neurons that facilitates Gαi/o -directed GTPase activating protein activity mediated by the Gβ5/R7-RGS complex. Knockout of R7bp diminishes scratching responses to multiple cutaneously applied and intrathecally-administered pruritogens in mice. Knock-in to mice of a GTPase activating protein-insensitive mutant of Gαo (Gnao1 G184S/+) produces a similar pruriceptive phenotype. The pruriceptive defect in R7bp knockout mice was rescued in double knockout mice also lacking Oprk1, encoding the G protein-coupled kappa-opioid receptor whose activation is known to inhibit itch sensation. In a model of atopic dermatitis (eczema), R7bp knockout mice showed diminished scratching behavior and enhanced sensitivity to kappa opioid agonists. Taken together, our results indicate that R7bp is a key regulator of itch sensation and suggest the potential targeting of R7bp-dependent GTPase activating protein activity as a novel therapeutic strategy for pathological itch.

Original languageEnglish (US)
Pages (from-to)931-944
Number of pages14
JournalPain
Volume158
Issue number5
DOIs
StatePublished - May 1 2017

Profile

GTPase-Activating Proteins
GTP-Binding Proteins
Knockout Mice
Atopic Dermatitis
Neurons
kappa Opioid Receptor
Uremia
Cell Surface Receptors
Sensory Receptor Cells
Dermatitis
Opioid Analgesics
Liver Diseases
Spinal Cord
Membrane Proteins
Chronic Disease
Phenotype
Skin
Mutation

ASJC Scopus subject areas

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Pandey, M., Zhang, J. H., Mishra, S. K., Adikaram, P. R., Harris, B., Kahler, J. F., ... Simonds, W. F. (2017). A central role for R7bp in the regulation of itch sensation. Pain, 158(5), 931-944. DOI: 10.1097/j.pain.0000000000000860

A central role for R7bp in the regulation of itch sensation. / Pandey, Mritunjay; Zhang, Jian Hua; Mishra, Santosh K.; Adikaram, Poorni R.; Harris, Benjamin; Kahler, John F.; Loshakov, Anna; Sholevar, Roxanne; Genis, Allison; Kittock, Claire; Kabat, Juraj; Ganesan, Sundar; Neubig, Richard R.; Hoon, Mark A.; Simonds, William F.

In: Pain, Vol. 158, No. 5, 01.05.2017, p. 931-944.

Research output: Contribution to journalArticle

Pandey, M, Zhang, JH, Mishra, SK, Adikaram, PR, Harris, B, Kahler, JF, Loshakov, A, Sholevar, R, Genis, A, Kittock, C, Kabat, J, Ganesan, S, Neubig, RR, Hoon, MA & Simonds, WF 2017, 'A central role for R7bp in the regulation of itch sensation' Pain, vol 158, no. 5, pp. 931-944. DOI: 10.1097/j.pain.0000000000000860
Pandey M, Zhang JH, Mishra SK, Adikaram PR, Harris B, Kahler JF et al. A central role for R7bp in the regulation of itch sensation. Pain. 2017 May 1;158(5):931-944. Available from, DOI: 10.1097/j.pain.0000000000000860

Pandey, Mritunjay; Zhang, Jian Hua; Mishra, Santosh K.; Adikaram, Poorni R.; Harris, Benjamin; Kahler, John F.; Loshakov, Anna; Sholevar, Roxanne; Genis, Allison; Kittock, Claire; Kabat, Juraj; Ganesan, Sundar; Neubig, Richard R.; Hoon, Mark A.; Simonds, William F. / A central role for R7bp in the regulation of itch sensation.

In: Pain, Vol. 158, No. 5, 01.05.2017, p. 931-944.

Research output: Contribution to journalArticle

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