Increased thrombospondin-4 after nerve injury mediates disruption of intracellular calcium signaling in primary sensory neurons

Yuan Guo, Zhiyong Zhang, Hsiang en Wu, Z. David Luo, Quinn H. Hogan, Bin Pan

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Painful nerve injury disrupts Ca2+ signaling in primary sensory neurons by elevating plasma membrane Ca2+-ATPase (PMCA) function and depressing sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) function, which decreases endoplasmic reticulum (ER) Ca2+ stores and stimulates store-operated Ca2+ entry (SOCE). The extracellular matrix glycoprotein thrombospondin-4 (TSP4), which is increased after painful nerve injury, decreases Ca2+ current (ICa) through high-voltage–activated Ca2+ channels and increases ICa through low-voltage–activated Ca2+ channels in dorsal root ganglion neurons, which are events similar to the effect of nerve injury. We therefore examined whether TSP4 plays a critical role in injury-induced disruption of intracellular Ca2+ signaling. We found that TSP4 increases PMCA activity, inhibits SERCA, depletes ER Ca2+ stores, and enhances store-operated Ca2+ influx. Injury-induced changes of SERCA and PMCA function are attenuated in TSP4 knock-out mice. Effects of TSP4 on intracellular Ca2+ signaling are attenuated in voltage-gated Ca2+ channel α2δ1 subunit (Cavα2δ1) conditional knock-out mice and are also Protein Kinase C (PKC) signaling dependent. These findings suggest that TSP4 elevation may contribute to the pathogenesis of chronic pain following nerve injury by disrupting intracellular Ca2+ signaling via interacting with the Cavα2δ1 and the subsequent PKC signaling pathway. Controlling TSP4 mediated intracellular Ca2+ signaling in peripheral sensory neurons may be a target for analgesic drug development for neuropathic pain.

Original languageEnglish (US)
Pages (from-to)292-304
Number of pages13
StatePublished - May 1 2017
Externally publishedYes


  • Ca stores and stimulates store-operated Ca entry
  • Intracellular calcium signaling
  • Neuropathic pain
  • Plasma membrane Ca-ATPase
  • Sarco-endoplasmic reticulum Ca-ATPase
  • Thrombospondin-4

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience


Dive into the research topics of 'Increased thrombospondin-4 after nerve injury mediates disruption of intracellular calcium signaling in primary sensory neurons'. Together they form a unique fingerprint.

Cite this