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

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 (I_Ca) through high-voltage–activated Ca²⁺ channels and increases I_Ca 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 (Ca_vα₂δ₁) 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 Ca_vα₂δ₁ 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.