title: Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype.
abstract: The voltage-gated sodium channel Na(v)1.8 is known to function in the transmission of pain signals induced by cold, heat, and mechanical stimuli. Sequence variants of human Na(v)1.8 have been linked to altered cardiac conduction. We identified an allele of Scn10a encoding the α-subunit of Na(v)1.8 among mice homozygous for N-ethyl-N-nitrosourea-induced mutations. The allele creates a dominant neurobehavioral phenotype termed Possum, characterized by transient whole-body tonic immobility induced by pinching the skin at the back of the neck ("scruffing"). The Possum mutation enhanced Na(v)1.8 sodium currents and neuronal excitability and heightened sensitivity of mutants to cold stimuli. Striking electroencephalographic changes were observed concomitant with the scruffing-induced behavioral change. In addition, electrocardiography demonstrated that Possum mice exhibited marked sinus bradycardia and R-R variability upon scruffing, abrogated by infusion of atropine. However, atropine failed to prevent or mitigate the tonic immobility response. Hyperactive sodium conduction via Na(v)1.8 thus leads to a complex neurobehavioral phenotype, which resembles catatonia in schizophrenic humans and tonic immobility in other mammals upon application of a discrete stimulus; no other form of mechanosensory stimulus could induce the immobility phenotype. Our data confirm the involvement of Na(v)1.8 in transducing pain initiated by cold and additionally implicate Na(v)1.8 in previously unknown functions in the central nervous system and heart.
authors.affiliation: Department of Genetics, and Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Blasius
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Dubin
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Petrus
authors.forename: Byung-Kwan
authors.initials: BK
authors.lastname: Lim
authors.forename: Anna
authors.initials: A
authors.lastname: Narezkina
authors.forename: José R
authors.initials: JR
authors.lastname: Criado
authors.forename: Derek N
authors.initials: DN
authors.lastname: Wills
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.forename: Eva Marie Y
authors.initials: EM
authors.lastname: Moresco
authors.forename: Cindy
authors.initials: C
authors.lastname: Ehlers
authors.forename: Kirk U
authors.initials: KU
authors.lastname: Knowlton
authors.forename: Ardem
authors.initials: A
authors.lastname: Patapoutian
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001919:Bradycardia / Q000235:genetics; D004562:Electrocardiography; D004569:Electroencephalography; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D062559:NAV1.8 Voltage-Gated Sodium Channel; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C568318:Scn10a protein, mouse; D015222:Sodium Channels; D001285:Atropine
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