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Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity
Ming-Dong Zhang, … , Tibor Harkany, Tomas Hökfelt
Ming-Dong Zhang, … , Tibor Harkany, Tomas Hökfelt
Published June 12, 2018
Citation Information: J Clin Invest. 2018;128(9):3757-3768. https://doi.org/10.1172/JCI120913.
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Research Article Neuroscience Article has an altmetric score of 3

Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity

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Abstract

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.

Authors

Ming-Dong Zhang, Jie Su, Csaba Adori, Valentina Cinquina, Katarzyna Malenczyk, Fatima Girach, Changgeng Peng, Patrik Ernfors, Peter Löw, Lotta Borgius, Ole Kiehn, Masahiko Watanabe, Mathias Uhlén, Nicholas Mitsios, Jan Mulder, Tibor Harkany, Tomas Hökfelt

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Figure 3

Generation of Necab2–/– mice and antibody validation.

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Generation of Necab2–/– mice and antibody validation.
(A) Construct for ...
(A) Construct for KO-first, promoter-driven Necab2–/– [Necab2(tm1a)] mice. The primers (blue lines indicate locations) used for genotyping are shown together with PCR products from WT (lanes 2 and 3), heterozygous (lane 1), and Necab2–/– (lanes 4 and 5) offspring. F, forward; R, reverse. (B) Staining pattern of previously used anti-NECAB2 antibody (HPA013998) in DRGs (green) and spinal cord (red) from WT and Necab2–/– mice. Scale bar: 100 μm. (C) Comparison of human NECAB2 protein epitope signature tags (PrESTs) with murine NECAB1 and NECAB2. (D) Western blots of NECAB2 with spinal cord lysates from WT and Necab2–/– mice using HPA013998 and HPA014144 anti-NECAB2 antibodies. Note that antibody HPA014144 has an unspecific band (asterisk) between 2 specific bands. Representative data from 2 WT and 4 Necab2–/– mice are shown. Another nonspecific band occurred above 100 kDa and is also indicated with an asterisk.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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