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.
Knockout of R7bp significantly impairs acute and chronic itch sensation, suggesting inhibition of R7bp function could represent a novel therapeutic strategy for pathological itch.
aMetabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Dr. Loshakov is now with the The Commonwealth Medical College, Scranton, PA, USA and Dr. Sholevar is now with the Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
bDepartment of Molecular Biomedical Sciences, North Carolina State University, College of Veterinary Medicine, Raleigh, NC, USA
cResearch Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
dDepartment of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
eMolecular Genetics Unit, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
Corresponding author. Address: National Institutes of Health, Bldg 10 Room 8C-101, 10 Center Dr MSC 1752, Bethesda, MD 20892-1752, USA. Tel.: 301-496-9299; fax: 301-480-3214. E-mail address: firstname.lastname@example.org (W. F. Simonds).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received October 31, 2016
Received in revised form December 16, 2016
Accepted January 18, 2017