title: The molecular basis of acid insensitivity in the African naked mole-rat.
abstract: Acid evokes pain by exciting nociceptors; the acid sensors are proton-gated ion channels that depolarize neurons. The naked mole-rat (Heterocephalus glaber) is exceptional in its acid insensitivity, but acid sensors (acid-sensing ion channels and the transient receptor potential vanilloid-1 ion channel) in naked mole-rat nociceptors are similar to those in other vertebrates. Acid inhibition of voltage-gated sodium currents is more profound in naked mole-rat nociceptors than in mouse nociceptors, however, which effectively prevents acid-induced action potential initiation. We describe a species-specific variant of the nociceptor sodium channel Na(V)1.7, which is potently blocked by protons and can account for acid insensitivity in this species. Thus, evolutionary pressure has selected for an Na(V)1.7 gene variant that tips the balance from proton-induced excitation to inhibition of action potential initiation to abolish acid nociception.
authors.affiliation: Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Berlin-Buch, Germany. ewan.smith@mdc-berlin.de
authors.forename: Ewan St John
authors.initials: ES
authors.lastname: Smith
authors.forename: Damir
authors.initials: D
authors.lastname: Omerbašić
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Lechner
authors.forename: Gireesh
authors.initials: G
authors.lastname: Anirudhan
authors.forename: Liudmila
authors.initials: L
authors.lastname: Lapatsina
authors.forename: Gary R
authors.initials: GR
authors.lastname: Lewin
mesh_terms: D062565:Acid Sensing Ion Channels; D000143:Acids / Q000378:metabolism / Q000494:pharmacology*; D000200:Action Potentials; D020816:Amino Acid Motifs; D000818:Animals; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology; D051379:Mice; D019577:Mole Rats / Q000235:genetics / Q000502:physiology*; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D059225:Nociception / Q000502:physiology*; D051381:Rats; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D062565:Acid Sensing Ion Channels; D000143:Acids; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C503479:Scn9a protein, mouse; D015222:Sodium Channels; D050916:TRPV Cation Channels