title: Transient receptor potential channel ankyrin-1 is not a cold sensor for autonomic thermoregulation in rodents.
abstract: The rodent transient receptor potential ankyrin-1 (TRPA1) channel has been hypothesized to serve as a temperature sensor for thermoregulation in the cold. We tested this hypothesis by using deletion of the Trpa1 gene in mice and pharmacological blockade of the TRPA1 channel in rats. In both Trpa1(-/-) and Trpa1(+/+) mice, severe cold exposure (8°C) resulted in decreases of skin and deep body temperatures to ∼8°C and 13°C, respectively, both temperatures being below the reported 17°C threshold temperature for TRPA1 activation. Under these conditions, Trpa1(-/-) mice had the same dynamics of body temperature as Trpa1(+/+) mice and showed no weakness in the tail skin vasoconstriction response or thermogenic response to cold. In rats, the effects of pharmacological blockade were studied by using two chemically unrelated TRPA1 antagonists: the highly potent and selective compound A967079, which had been characterized earlier, and the relatively new compound 43 ((4R)-1,2,3,4-tetrahydro-4-[3-(3-methoxypropoxy)phenyl]-2-thioxo-5H-indeno[1,2-d]pyrimidin-5-one), which we further characterized in the present study and found to be highly potent (IC50 against cold of ∼8 nm) and selective. Intragastric administration of either antagonist at 30 mg/kg before severe (3°C) cold exposure did not affect the thermoregulatory responses (deep body and tail skin temperatures) of rats, even though plasma concentrations of both antagonists well exceeded their IC50 value at the end of the experiment. In the same experimental setup, blocking the melastatin-8 (TRPM8) channel with AMG2850 (30 mg/kg) attenuated cold-defense mechanisms and led to hypothermia. We conclude that TRPA1 channels do not drive autonomic thermoregulatory responses to cold in rodents.
authors.affiliation: Systemic Inflammation Laboratory (FeverLab), Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, Department of Pathophysiology and Gerontology, Medical School, University of Pecs, Pecs, H-7624, Hungary, Department of Neuroscience, Amgen Inc., Thousand Oaks, California 91320, Department of Pharmacology and Pharmacotherapy, Medical School, University of Pecs, Pecs, H-7624, Hungary, Janos Szentagothai Research Centre, University of Pecs, Pecs, H-7624, Hungary, and Neuroscience Research, Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, Illinois 60064.
authors.forename: Cristiane
authors.initials: C
authors.lastname: de Oliveira
authors.forename: Andras
authors.initials: A
authors.lastname: Garami
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.forename: Eszter
authors.initials: E
authors.lastname: Pakai
authors.forename: Valeria
authors.initials: V
authors.lastname: Tekus
authors.forename: Krisztina
authors.initials: K
authors.lastname: Pohoczky
authors.forename: Beth D
authors.initials: BD
authors.lastname: Youngblood
authors.forename: Weiya
authors.initials: W
authors.lastname: Wang
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Erika
authors.initials: E
authors.lastname: Pinter
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: Andrej A
authors.initials: AA
authors.lastname: Romanovsky
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology*; D001833:Body Temperature Regulation / Q000187:drug effects / Q000235:genetics*; D016466:CHO Cells; D003080:Cold Temperature; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010091:Oximes / Q000097:blood / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012881:Skin Temperature / Q000187:drug effects; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors; D013697:Thermosensing / Q000187:drug effects / Q000235:genetics*
chemical_list: C560402:A 967079; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010091:Oximes; C547760:TRAP-1 protein, mouse; D050053:TRPM Cation Channels; C116297:Trpm1 protein, mouse
keywords: TRPA1; TRPM8; cold exposure; hypothermia; thermoregulation