The transient receptor potential channel TRPM8 is inhibited via the alpha 2A adrenoreceptor signaling pathway.
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.
Bavencoffe
Alexis
A
INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
Gkika
Dimitra
D
INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
Kondratskyi
Artem
A
Bogomoletz Institute of Physiology and International Center of Molecular Physiology of the National Academy of Sciences of Ukraine, Kyiv, Ukraine.
Beck
Benjamin
B
INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
Borowiec
Anne-Sophie
AS
INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
Bidaux
Gabriel
G
INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
Busserolles
Jérôme
J
INSERM, U766, Faculté de Médecine, Université d'Auvergne, 63001 Clermont-Ferrand, France.
Eschalier
Alain
A
INSERM, U766, Faculté de Médecine, Université d'Auvergne, 63001 Clermont-Ferrand, France.
Shuba
Yaroslav
Y
Bogomoletz Institute of Physiology and International Center of Molecular Physiology of the National Academy of Sciences of Ukraine, Kyiv, Ukraine.
Skryma
Roman
R
INSERM U800, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université des Sciences et Technologies de Lille (USTL), F59655 Villeneuve d'Ascq, France.
Prevarskaya
Natalia
N
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.
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
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