Cortés-Montero, ElsaRodríguez-Muñoz, MaríaRuiz-Cantero, María Del CarmenCobos, Enrique JoséSánchez-Blázquez, PilarGarzón-Niño, Javier2022-09-222022-09-222020-12-28Cortés-Montero E, Rodríguez-Muñoz M, Ruiz-Cantero MDC, Cobos EJ, Sánchez-Blázquez P, Garzón-Niño J. Calmodulin Supports TRPA1 Channel Association with Opioid Receptors and Glutamate NMDA Receptors in the Nervous Tissue. Int J Mol Sci. 2020 Dec 28;22(1):2291661-6596http://hdl.handle.net/10668/4108Transient receptor potential ankyrin member 1 (TRPA1) belongs to the family of thermo TRP cation channels that detect harmful temperatures, acids and numerous chemical pollutants. TRPA1 is expressed in nervous tissue, where it participates in the genesis of nociceptive signals in response to noxious stimuli and mediates mechanical hyperalgesia and allodynia associated with different neuropathies. The glutamate N-methyl-d-aspartate receptor (NMDAR), which plays a relevant role in allodynia to mechanical stimuli, is connected via histidine triad nucleotide-binding protein 1 (HINT1) and type 1 sigma receptor (σ1R) to mu-opioid receptors (MORs), which mediate the most potent pain relief. Notably, neuropathic pain causes a reduction in MOR antinociceptive efficacy, which can be reversed by blocking spinal NMDARs and TRPA1 channels. Thus, we studied whether TRPA1 channels form complexes with MORs and NMDARs that may be implicated in the aforementioned nociceptive signals. Our data suggest that TRPA1 channels functionally associate with MORs, delta opioid receptors and NMDARs in the dorsal root ganglia, the spinal cord and brain areas. These associations were altered in response to pharmacological interventions and the induction of inflammatory and also neuropathic pain. The MOR-TRPA1 and NMDAR-TRPA1 associations do not require HINT1 or σ1R but appear to be mediated by calcium-activated calmodulin. Thus, TRPA1 channels may associate with NMDARs to promote ascending acute and chronic pain signals and to control MOR antinociception.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Transient receptor potential A1Mu opioid receptorCalmodulinGlutamate NMDA receptorNeuropathic painInflammatory painHyperalgesiaAntinociceptionDorsal root gangliaSpinal cordCanal catiónico TRPA1Receptores opioides muCalmodulinaReceptores de glutamatoNeuralgiaHiperalgesiaGanglios espinalesMédula espinalMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Calcium-Binding Proteins::Intracellular Calcium-Sensing Proteins::CalmodulinMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathological Conditions, Anatomical::Constriction, PathologicMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Aldehydes::FormaldehydeMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Amino Acids, Acidic::Glutamates::Glutamic AcidMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::InflammationMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Anatomy::Nervous System::Nerve TissueMedical Subject Headings::Diseases::Nervous System Diseases::Neurologic Manifestations::Pain::NeuralgiaMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Organ SpecificityMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Protein BindingMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Protein SubunitsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::Ion Channels::Ligand-Gated Ion Channels::Receptors, Ionotropic Glutamate::Receptors, N-Methyl-D-AspartateMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, OpioidMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Membrane Transport Proteins::Ion Channels::Calcium Channels::TRPP Cation ChannelsMedical Subject Headings::Diseases::Nervous System Diseases::Neurologic Manifestations::Sensation Disorders::Somatosensory Disorders::HyperalgesiaMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, Opioid::Receptors, sigmaMedical Subject Headings::Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::Perception::Pain Perception::NociceptionMedical Subject Headings::Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::Perception::Pain Perception::NociceptionMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::AnkyrinsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Amino Acids, Cyclic::HistidineMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, Opioid::Receptors, Opioid, deltaMedical Subject Headings::Diseases::Nervous System Diseases::Neurologic Manifestations::Pain::Chronic PainMedical Subject Headings::Anatomy::Nervous System::Ganglia::Ganglia, Sensory::Ganglia, SpinalMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::Spinal CordMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Central Nervous System Agents::AnalgesicsMedical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::NucleotidesMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Amino Acids, Acidic::GlutamatesMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Toxic Actions::Environmental PollutantsMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brainresearch article33379368Acceso abierto10.3390/ijms220102291422-0067PMC7795679