Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity

Ming Dong Zhang, Jie Su, C. Ádori, 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

Research output: Contribution to journalReview article

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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.

Original languageEnglish
Pages (from-to)3757-3768
Number of pages12
JournalJournal of Clinical Investigation
Volume128
Issue number9
DOIs
Publication statusPublished - Aug 31 2018

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EF Hand Motifs
Carrier Proteins
Hypersensitivity
Pain
Spinal Ganglia
Interneurons
Single-Cell Analysis
Inflammation
RNA Sequence Analysis
Neurons
Peripheral Nerve Injuries
Nociceptors
Mechanoreceptors
Spinal Nerve Roots
Brain-Derived Neurotrophic Factor
Hair
Synapses
Protein Kinase C
Glutamic Acid
Spinal Cord

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhang, M. D., Su, J., Ádori, C., Cinquina, V., Malenczyk, K., Girach, F., ... Hökfelt, T. (2018). Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity. Journal of Clinical Investigation, 128(9), 3757-3768. https://doi.org/10.1172/JCI120913

Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity. / Zhang, Ming Dong; Su, Jie; Ádori, C.; Cinquina, Valentina; Malenczyk, Katarzyna; Girach, Fatima; Peng, Changgeng; Ernfors, Patrik; Löw, Peter; Borgius, Lotta; Kiehn, Ole; Watanabe, Masahiko; Uhlén, Mathias; Mitsios, Nicholas; Mulder, Jan; Harkany, Tibor; Hökfelt, Tomas.

In: Journal of Clinical Investigation, Vol. 128, No. 9, 31.08.2018, p. 3757-3768.

Research output: Contribution to journalReview article

Zhang, MD, Su, J, Ádori, C, Cinquina, V, Malenczyk, K, Girach, F, Peng, C, Ernfors, P, Löw, P, Borgius, L, Kiehn, O, Watanabe, M, Uhlén, M, Mitsios, N, Mulder, J, Harkany, T & Hökfelt, T 2018, 'Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity', Journal of Clinical Investigation, vol. 128, no. 9, pp. 3757-3768. https://doi.org/10.1172/JCI120913
Zhang, Ming Dong ; Su, Jie ; Ádori, C. ; Cinquina, Valentina ; Malenczyk, Katarzyna ; Girach, Fatima ; Peng, Changgeng ; Ernfors, Patrik ; Löw, Peter ; Borgius, Lotta ; Kiehn, Ole ; Watanabe, Masahiko ; Uhlén, Mathias ; Mitsios, Nicholas ; Mulder, Jan ; Harkany, Tibor ; Hökfelt, Tomas. / Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 9. pp. 3757-3768.
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AU - Zhang, Ming Dong

AU - Su, Jie

AU - Ádori, C.

AU - Cinquina, Valentina

AU - Malenczyk, Katarzyna

AU - Girach, Fatima

AU - Peng, Changgeng

AU - Ernfors, Patrik

AU - Löw, Peter

AU - Borgius, Lotta

AU - Kiehn, Ole

AU - Watanabe, Masahiko

AU - Uhlén, Mathias

AU - Mitsios, Nicholas

AU - Mulder, Jan

AU - Harkany, Tibor

AU - Hökfelt, Tomas

PY - 2018/8/31

Y1 - 2018/8/31

N2 - 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.

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