Thrombospondin-4 divergently regulates voltage-gated Ca2+ channel subtypes in sensory neurons after nerve injury

Bin Pan, Yuan Guo, Hsiang En Wu, John Park, Van Nancy Trinh, Z. David Luo, Quinn H. Hogan

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Loss of high-voltage-activated (HVA) calcium current (I Ca) and gain of low-voltage-activated (LVA) I Ca after painful peripheral nerve injury cause elevated excitability in sensory neurons. Nerve injury is also accompanied by increased expression of the extracellular matrix glycoprotein thrombospondin-4 (TSP4), and interruption of TSP4 function can reverse or prevent behavioral hypersensitivity after injury. We therefore investigated TSP4 regulation of I Ca in dorsal root ganglion (DRG) neurons. During depolarization adequate to activate HVA I Ca, TSP4 decreases both N- and L-type I Ca and the associated intracellular calcium transient. In contrast, TSP4 increases I Ca and the intracellular calcium signal after low-voltage depolarization, which we confirmed is due to I Ca through T-type channels. These effects are blocked by gabapentin, which ameliorates neuropathic pain by targeting the α 2 δ 1 calcium subunit. Injury-induced changes of HVA and LVA I Ca are attenuated in TSP4 knockout mice. In the neuropathic pain model of spinal nerve ligation, TSP4 application did not further regulate I Ca of injured DRG neurons. Taken together, these findings suggest that elevated TSP4 after peripheral nerve injury may contribute to hypersensitivity of peripheral sensory systems by decreasing HVA and increasing LVA in DRG neurons by targeting the α 2 δ 1 calcium subunit. Controlling TSP4 overexpression in peripheral sensory neurons may be a target for analgesic drug development for neuropathic pain.

Original languageEnglish (US)
Pages (from-to)2068-2080
Number of pages13
JournalPain
Volume157
Issue number9
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Keywords

  • Neuropathic pain
  • Thrombospondin-4
  • Voltage-gated calcium channels

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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