Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity

J Clin Invest. 2018 Aug 31;128(9):3757-3768. doi: 10.1172/JCI120913. Epub 2018 Jul 30.


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.

Keywords: Calcium; Neuroscience; Pain; Synapses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Calcium-Binding Proteins / deficiency
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Calcium-Binding Proteins / physiology*
  • Down-Regulation
  • Eye Proteins / genetics
  • Eye Proteins / physiology*
  • Female
  • Ganglia, Spinal / physiopathology
  • Hyperalgesia / etiology*
  • Hyperalgesia / genetics
  • Hyperalgesia / physiopathology*
  • Inflammation / physiopathology
  • Interneurons / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nociceptors / physiology
  • Pain / etiology*
  • Pain / genetics
  • Pain / physiopathology*
  • Peripheral Nerve Injuries / genetics
  • Peripheral Nerve Injuries / physiopathology
  • Secretagogins / deficiency
  • Secretagogins / genetics
  • Secretagogins / metabolism
  • Spinal Cord / physiopathology
  • Spinal Cord Dorsal Horn / physiopathology


  • Bdnf protein, mouse
  • Brain-Derived Neurotrophic Factor
  • Calcium-Binding Proteins
  • Eye Proteins
  • NECAB2 protein, mouse
  • Necab3 protein, mouse
  • SCGN protein, mouse
  • Secretagogins