Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity
| Autor: | Jan Mulder, Tibor Harkany, Katarzyna Malenczyk, Tomas Hökfelt, Fatima Girach, Mathias Uhlén, Masahiko Watanabe, Lotta Borgius, Ming-Dong Zhang, Valentina Cinquina, Csaba Adori, Changgeng Peng, Peter Löw, Patrik Ernfors, Ole Kiehn, Jie Su, Nicholas Mitsios |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Spinal Cord Dorsal Horn Down-Regulation Pain Synapse 03 medical and health sciences Glutamatergic Mice 0302 clinical medicine Neurotrophic factors Interneurons Peripheral Nerve Injuries Ganglia Spinal Medicine Animals Eye Proteins Inflammation Mice Knockout business.industry Brain-Derived Neurotrophic Factor Calcium-Binding Proteins Glutamate receptor Nociceptors General Medicine Spinal cord Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Spinal Cord Hyperalgesia Peripheral nerve injury Nociceptor Excitatory postsynaptic potential Female business Neuroscience 030217 neurology & neurosurgery Secretagogins Research Article |
| Zdroj: | Journal of Clinical Investigation |
| Popis: | Pain signals are transmitted by multisynaptic glutamatergic pathways. Their first synapse between primary nociceptors and excitatory spinal interneurons gates the sensory load. In this pathway, glutamate release is orchestrated by Ca2+-sensor proteins, with N-terminal EF-hand Ca2+-binding protein 2 (NECAB2) being particular abundant. However, neither the importance of NECAB2+ neuronal contingents in dorsal root ganglia (DRGs) and spinal cord nor the function determination by NECAB2 has been defined. A combination of histochemical analyses and single-cell RNA-sequencing showed NECAB2 in small- and medium-sized C- and Aδ D-hair low-threshold mechanoreceptors in DRGs, as well as in protein kinase C γ excitatory spinal interneurons. NECAB2 was downregulated by peripheral nerve injury, leading to the hypothesis that NECAB2 loss of function could limit pain sensation. Indeed, Necab2-/- mice reached a pain-free state significantly faster after peripheral inflammation than did WT littermates. Genetic access to transiently activated neurons revealed that a mediodorsal cohort of NECAB2+ neurons mediates inflammatory pain in the mouse spinal dorsal horn. Here, besides dampening excitatory transmission in spinal interneurons, NECAB2 limited pronociceptive brain-derived neurotrophic factor (BDNF) release from sensory afferents. Hoxb8-dependent reinstatement of NECAB2 expression in Necab2-/- mice then demonstrated that spinal and DRG NECAB2 alone could control inflammation-induced sensory hypersensitivity. Overall, we identify NECAB2 as a critical component of pronociceptive pain signaling, whose inactivation offers substantial pain relief. |
| Databáze: | OpenAIRE |
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