title: A central role for R7bp in the regulation of itch sensation.
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.
authors.affiliation: Metabolic 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.
authors.forename: Mritunjay
authors.initials: M
authors.lastname: Pandey
authors.affiliation: Metabolic 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.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biomedical Sciences, North Carolina State University, College of Veterinary Medicine, Raleigh, NC, USA.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Mishra
authors.affiliation: Metabolic 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.
authors.forename: Poorni R
authors.initials: PR
authors.lastname: Adikaram
authors.affiliation: Metabolic 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.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Harris
authors.affiliation: Metabolic 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.
authors.forename: John F
authors.initials: JF
authors.lastname: Kahler
authors.affiliation: Metabolic 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Loshakov
authors.affiliation: Metabolic 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.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Sholevar
authors.affiliation: Metabolic 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.
authors.forename: Allison
authors.initials: A
authors.lastname: Genis
authors.affiliation: Metabolic 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.
authors.forename: Claire
authors.initials: C
authors.lastname: Kittock
authors.affiliation: Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Juraj
authors.initials: J
authors.lastname: Kabat
authors.affiliation: Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sundar
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
authors.affiliation: Molecular Genetics Unit, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hoon
authors.affiliation: Metabolic 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.
authors.forename: William F
authors.initials: WF
authors.lastname: Simonds
mesh_terms: D000818:Animals; D002164:Camphor / Q000031:analogs & derivatives / Q000633:toxicity; D002478:Cells, Cultured; D002867:Chromones / Q000633:toxicity; D019332:Endothelin-1 / Q000633:toxicity; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000473:pathology; D019886:Gastrin-Releasing Peptide / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D020097:Natriuretic Peptide, Brain / Q000633:toxicity; D059225:Nociception / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology; D011537:Pruritus / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D011597:Psychomotor Performance / Q000502:physiology; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000378:metabolism; D012677:Sensation / Q000235:genetics*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology
chemical_list: C479984:3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano(2,3-f)chromone; D002867:Chromones; D019332:Endothelin-1; C499440:R7BP protein, mouse; D020710:RGS Proteins; D017473:Receptors, Opioid, kappa; D020097:Natriuretic Peptide, Brain; D002164:Camphor; D019886:Gastrin-Releasing Peptide; C000594262:GNAO1 protein, mouse; D019206:GTP-Binding Protein alpha Subunits, Gi-Go