title: Low-cost functional plasticity of TRPV1 supports heat tolerance in squirrels and camels.
abstract: The ability to sense heat is crucial for survival. Increased heat tolerance may prove beneficial by conferring the ability to inhabit otherwise prohibitive ecological niches. This phenomenon is widespread and is found in both large and small animals. For example, ground squirrels and camels can tolerate temperatures more than 40 °C better than many other mammalian species, yet a molecular mechanism subserving this ability is unclear. Transient receptor potential vanilloid 1 (TRPV1) is a polymodal ion channel involved in the detection of noxious thermal and chemical stimuli by primary afferents of the somatosensory system. Here, we show that thirteen-lined ground squirrels (Ictidomys tridecemlineatus) and Bactrian camels (Camelus ferus) express TRPV1 orthologs with dramatically reduced temperature sensitivity. The loss of sensitivity is restricted to temperature and does not affect capsaicin or acid responses, thereby maintaining a role for TRPV1 as a detector of noxious chemical cues. We show that heat sensitivity can be reengineered in both TRPV1 orthologs by a single amino acid substitution in the N-terminal ankyrin-repeat domain. Conversely, reciprocal mutations suppress heat sensitivity of rat TRPV1, supporting functional conservation of the residues. Our studies suggest that squirrels and camels co-opt a common molecular strategy to adapt to hot environments by suppressing the efficiency of TRPV1-mediated heat detection at the level of somatosensory neurons. Such adaptation is possible because of the remarkable functional flexibility of the TRPV1 molecule, which can undergo profound tuning at the minimal cost of a single amino acid change.
authors.affiliation: Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Willem J
authors.initials: WJ
authors.lastname: Laursen
authors.affiliation: Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Eve R
authors.identifier: 0000-0002-0998-4363
authors.initials: ER
authors.lastname: Schneider
authors.affiliation: Department of Biology, University of Wisconsin, Oshkosh, WI 54901.
authors.forename: Dana K
authors.initials: DK
authors.lastname: Merriman
authors.affiliation: Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510; elena.gracheva@yale.edu slav.bagriantsev@yale.edu.
authors.forename: Sviatoslav N
authors.initials: SN
authors.lastname: Bagriantsev
authors.affiliation: Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510; elena.gracheva@yale.edu slav.bagriantsev@yale.edu.
authors.forename: Elena O
authors.initials: EO
authors.lastname: Gracheva
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017089:Ankyrin Repeat; D002162:Camelus / Q000502:physiology*; D002211:Capsaicin / Q000494:pharmacology; D017124:Conserved Sequence; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D012589:Sciuridae / Q000502:physiology*; D016415:Sequence Alignment; D050916:TRPV Cation Channels / Q000737:chemistry / Q000378:metabolism*; D000071436:Thermotolerance / Q000187:drug effects; D014981:Xenopus / Q000378:metabolism
chemical_list: D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D002211:Capsaicin
keywords: TRPV1; bactrian camel; sensory physiology; thermosensation; thirteen-lined ground squirrel