title: Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat.
abstract: The naked mole-rat is a subterranean rodent lacking several pain behaviors found in humans, rats, and mice. For example, nerve growth factor (NGF), an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked mole-rats. The sensitization of capsaicin-sensitive TRPV1 ion channels is necessary for NGF-induced hyperalgesia, but naked mole-rats have fully functional TRPV1 channels. We show that exposing isolated naked mole-rat nociceptors to NGF does not sensitize TRPV1. However, the naked mole-rat NGF receptor TrkA displays a reduced ability to engage signal transduction pathways that sensitize TRPV1. Between one- and three-amino-acid substitutions in the kinase domain of the naked mole-rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia. Our data suggest that evolution has selected for a TrkA variant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness.
authors.affiliation: Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Proteome Dynamics Group, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Damir
authors.initials: D
authors.lastname: Omerbašić
authors.affiliation: Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
authors.forename: Ewan St J
authors.initials: ES
authors.lastname: Smith
authors.affiliation: Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Moroni
authors.affiliation: Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Homfeld
authors.affiliation: Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Ole
authors.initials: O
authors.lastname: Eigenbrod
authors.affiliation: Department of Zoology and Entomology, University of Pretoria, Pretoria, Hatfield 0028, Republic of South Africa.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Bennett
authors.affiliation: Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Jane
authors.initials: J
authors.lastname: Reznick
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, UK.
authors.forename: Chris G
authors.initials: CG
authors.lastname: Faulkes
authors.affiliation: Proteome Dynamics Group, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Selbach
authors.affiliation: Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Excellence Cluster Neurocure, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany. Electronic address: glewin@mdc-berlin.de.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Lewin
mesh_terms: D000818:Animals; D005727:Ganglia, Spinal / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D019577:Mole Rats; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism; D010146:Pain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000072417:Protein Domains; D040901:Proteomics; D020917:Receptor, trkA / Q000737:chemistry / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D050916:TRPV Cation Channels; D020932:Nerve Growth Factor; D020917:Receptor, trkA
keywords: calcium imaging; capsaicin receptor; electrophysiology; hyperalgesia; nerve growth factor; nociceptor development; receptor kinase signaling; sensitization; transcriptome assembly