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

Painful nerve injury disrupts Ca signaling in primary sensory neurons by elevating plasma membrane Ca-ATPase (PMCA) function and depressing sarco-endoplasmic reticulum Ca-ATPase (SERCA) function, which decreases endoplasmic reticulum (ER) Ca stores and stimulates store-operated Ca entry (SOCE). The extracellular matrix glycoprotein thrombospondin-4 (TSP4), which is increased after painful nerve injury, decreases Ca current (I) through high-voltage-activated Ca channels and increases I through low-voltage-activated Ca 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 Ca signaling. We found that TSP4 increases PMCA activity, inhibits SERCA, depletes ER Ca stores, and enhances store-operated Ca influx. Injury-induced changes of SERCA and PMCA function are attenuated in TSP4 knock-out mice. Effects of TSP4 on intracellular Ca signaling are attenuated in voltage-gated Ca channel αδ subunit (Caαδ) 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 Ca signaling via interacting with the Caαδ and the subsequent PKC signaling pathway. Controlling TSP4 mediated intracellular Ca signaling in peripheral sensory neurons may be a target for analgesic drug development for neuropathic pain.