title: The transient receptor potential channel TRPM8 is inhibited via the alpha 2A adrenoreceptor signaling pathway.
abstract: The transient receptor potential channel melastatin member 8 (TRPM8) is expressed in sensory neurons, where it constitutes the main receptor of environmental innocuous cold (10-25 degrees C). Among several types of G protein-coupled receptors expressed in sensory neurons, G(i)-coupled alpha 2A-adrenoreceptor (alpha 2A-AR), is known to be involved in thermoregulation; however, the underlying molecular mechanisms remain poorly understood. Here we demonstrated that stimulation of alpha 2A-AR inhibited TRPM8 in sensory neurons from rat dorsal root ganglia (DRG). In addition, using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. We therefore propose that inhibition of TRPM8 through the alpha 2A-AR signaling cascade could constitute a new mechanism of modulation of thermosensation in both physiological and pathological conditions.
authors.affiliation: INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Bavencoffe
authors.affiliation: INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Gkika
authors.affiliation: Bogomoletz Institute of Physiology and International Center of Molecular Physiology of the National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Artem
authors.initials: A
authors.lastname: Kondratskyi
authors.affiliation: INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Beck
authors.affiliation: INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Borowiec
authors.affiliation: INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Bidaux
authors.affiliation: INSERM, U766, Faculté de Médecine, Université d'Auvergne, 63001 Clermont-Ferrand, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Busserolles
authors.affiliation: INSERM, U766, Faculté de Médecine, Université d'Auvergne, 63001 Clermont-Ferrand, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Eschalier
authors.affiliation: Bogomoletz Institute of Physiology and International Center of Molecular Physiology of the National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Shuba
authors.affiliation: INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
authors.forename: Roman
authors.initials: R
authors.lastname: Skryma
authors.affiliation: INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France. Electronic address: natacha.prevarskaya@univ-lille1.fr.
authors.forename: Natalia
authors.initials: N
authors.lastname: Prevarskaya
mesh_terms: D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D016296:Mutagenesis; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D050053:TRPM Cation Channels / Q000378:metabolism*; D013696:Temperature
chemical_list: C547768:ADRA2A protein, human; C547770:Adra2a protein, rat; D018341:Receptors, Adrenergic, alpha-2; D043562:Receptors, G-Protein-Coupled; D050053:TRPM Cation Channels; C498947:Trpm8 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases