PMID- 29893745 OWN - NLM STAT- MEDLINE DCOM- 20190924 LR - 20190925 IS - 1558-8238 (Electronic) IS - 0021-9738 (Print) IS - 0021-9738 (Linking) VI - 128 IP - 9 DP - 2018 Aug 31 TI - Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity. PG - 3757-3768 LID - 120913 [pii] LID - 10.1172/JCI120913 [doi] AB - 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 Adelta D-hair low-threshold mechanoreceptors in DRGs, as well as in protein kinase C gamma 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. FAU - Zhang, Ming-Dong AU - Zhang MD AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Su, Jie AU - Su J AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Adori, Csaba AU - Adori C AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Cinquina, Valentina AU - Cinquina V AD - Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria. FAU - Malenczyk, Katarzyna AU - Malenczyk K AD - Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria. FAU - Girach, Fatima AU - Girach F AD - Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria. FAU - Peng, Changgeng AU - Peng C AD - Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. FAU - Ernfors, Patrik AU - Ernfors P AD - Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. FAU - Low, Peter AU - Low P AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Borgius, Lotta AU - Borgius L AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Kiehn, Ole AU - Kiehn O AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Watanabe, Masahiko AU - Watanabe M AD - Hokkaido University School of Medicine, Sapporo, Japan. FAU - Uhlen, Mathias AU - Uhlen M AD - Science for Life Laboratory, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Mitsios, Nicholas AU - Mitsios N AD - Science for Life Laboratory, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Mulder, Jan AU - Mulder J AD - Science for Life Laboratory, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. FAU - Harkany, Tibor AU - Harkany T AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. AD - Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria. FAU - Hokfelt, Tomas AU - Hokfelt T AD - Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. LA - eng GR - UM1 OD023221/OD/NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180730 PL - United States TA - J Clin Invest JT - The Journal of clinical investigation JID - 7802877 RN - 0 (Bdnf protein, mouse) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Calcium-Binding Proteins) RN - 0 (Eye Proteins) RN - 0 (NECAB2 protein, mouse) RN - 0 (Necab3 protein, mouse) RN - 0 (SCGN protein, mouse) RN - 0 (Secretagogins) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Calcium-Binding Proteins/deficiency/genetics/metabolism/*physiology MH - Down-Regulation MH - Eye Proteins/genetics/*physiology MH - Female MH - Ganglia, Spinal/physiopathology MH - Hyperalgesia/*etiology/genetics/*physiopathology MH - Inflammation/physiopathology MH - Interneurons/physiology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Nociceptors/physiology MH - Pain/*etiology/genetics/*physiopathology MH - Peripheral Nerve Injuries/genetics/physiopathology MH - Secretagogins/deficiency/genetics/metabolism MH - Spinal Cord/physiopathology MH - Spinal Cord Dorsal Horn/physiopathology PMC - PMC6118643 OTO - NOTNLM OT - Calcium OT - Neuroscience OT - Pain OT - Synapses COIS- Conflict of interest: The authors have declared that no conflict of interest exists. EDAT- 2018/06/13 06:00 MHDA- 2019/09/26 06:00 PMCR- 2018/12/01 CRDT- 2018/06/13 06:00 PHST- 2018/03/07 00:00 [received] PHST- 2018/06/06 00:00 [accepted] PHST- 2018/06/13 06:00 [pubmed] PHST- 2019/09/26 06:00 [medline] PHST- 2018/06/13 06:00 [entrez] PHST- 2018/12/01 00:00 [pmc-release] AID - 120913 [pii] AID - 10.1172/JCI120913 [doi] PST - ppublish SO - J Clin Invest. 2018 Aug 31;128(9):3757-3768. doi: 10.1172/JCI120913. Epub 2018 Jul 30.