title: Increased thrombospondin-4 after nerve injury mediates disruption of intracellular calcium signaling in primary sensory neurons.
abstract: 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 ICathrough 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 α2δ1subunit (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 Cavα2δ1and 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.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States.
authors.forename: Hsiang-En
authors.initials: HE
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology & Perioperative Care, University of California Irvine, Irvine, CA 92697, United States; Department of Pharmacology, University of California Irvine, Irvine, CA 92697, United States.
authors.forename: Z David
authors.initials: ZD
authors.lastname: Luo
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States.
authors.forename: Quinn H
authors.initials: QH
authors.lastname: Hogan
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States. Electronic address: bpan@mcw.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Pan
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009437:Neuralgia / Q000378:metabolism; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism*; D013127:Spinal Nerves / Q000293:injuries*; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D019699:Thrombospondins; C101864:thrombospondin 4; D011493:Protein Kinase C; D053499:Plasma Membrane Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: Ca(2+) stores and stimulates store-operated Ca(2+) entry; Intracellular calcium signaling; Neuropathic pain; Plasma membrane Ca(2+)-ATPase; Sarco-endoplasmic reticulum Ca(2+)-ATPase; Thrombospondin-4