The ¿1 Receptor and the HINT1 Protein Control ¿2¿1 Binding to Glutamate NMDA Receptors: Implications in Neuropathic Pain
| Autor: | Pilar Sánchez-Blázquez, Javier Garzón-Niño, María Rodríguez-Muñoz, Elsa Cortés-Montero, Yara Onetti |
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| Přispěvatelé: | Ministerio de Ciencia e Innovación (España) |
| Rok vydání: | 2021 |
| Předmět: |
Male
Glutamic Acid Pharmacology Microbiology Biochemistry Periaqueductal gray Receptors N-Methyl-D-Aspartate Article Mice medicine Animals Receptors sigma Receptor Molecular Biology sigma receptor type 1 HINT1 protein Sigma-1 receptor Chemistry musculoskeletal neural and ocular physiology Glutamate receptor Nerve injury QR1-502 Allodynia nervous system Neuropathic pain NMDA receptor Neuralgia medicine.symptom psychological phenomena and processes mechanical allodynia |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Biomolecules Volume 11 Issue 11 Biomolecules, Vol 11, Iss 1681, p 1681 (2021) |
| Popis: | Nerve injury produces neuropathic pain through the binding of ¿2¿1 proteins to glutamate N-methyl-D-aspartate receptors (NMDARs). Notably, mice with a targeted deletion of the sigma 1 receptor (¿1R) gene do not develop neuropathy, whereas mice lacking the histidine triad nucleotide-binding protein 1 (Hint1) gene exhibit exacerbated allodynia. ¿1R antagonists more effectively diminish neuropathic pain of spinal origin when administered by intracerebroventricular injection than systemically. Thus, in mice subjected to unilateral sciatic nerve chronic constriction injury (CCI), we studied the participation of ¿1Rs and HINT1 proteins in the formation of ¿2¿1-NMDAR complexes within the supraspinal periaqueductal gray (PAG). We found that ¿1 peptides required ¿1Rs in order to interact with the NMDAR NR1 variant that contains the cytosolic C1 segment. ¿1R antagonists or low calcium levels provoke the dissociation of ¿1R-NR1 C1 dimers, while they barely affect the integrity of ¿1-¿1R-NR1 C1 trimers. However, HINT1 does remove ¿1 peptides from the trimer, thereby facilitating the subsequent dissociation of ¿1Rs from NMDARs. In ¿1R-/- mice, CCI does not promote the formation of NMDAR-¿2¿1 complexes and allodynia does not develop. The levels of ¿2¿1-¿1R-NMDAR complexes increase in HINT1-/- mice and after inducing CCI, degradation of ¿2¿1 proteins is observed. Notably, ¿1R antagonists but not gabapentinoids alleviate neuropathic pain in these mice. During severe neuropathy, the metabolism of ¿2¿1 proteins may account for the failure of many patients to respond to gabapentinoids. Therefore, ¿1Rs promote and HINT1 proteins hinder the formation ¿2¿1-NMDAR complexes in the PAG, and hence, the appearance of mechanical allodynia depends on the interplay between these proteins. This work was supported by MICINN Plan Nacional I+D+i [grant number RT 2018-093677-B-100]. |
| Databáze: | OpenAIRE |
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