title: Thrombospondin-4 divergently regulates voltage-gated Ca2+ channel subtypes in sensory neurons after nerve injury.
abstract: Loss of high-voltage-activated (HVA) calcium current (ICa) and gain of low-voltage-activated (LVA) ICa 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 ICa in dorsal root ganglion (DRG) neurons. During depolarization adequate to activate HVA ICa, TSP4 decreases both N- and L-type ICa and the associated intracellular calcium transient. In contrast, TSP4 increases ICa and the intracellular calcium signal after low-voltage depolarization, which we confirmed is due to ICa through T-type channels. These effects are blocked by gabapentin, which ameliorates neuropathic pain by targeting the α2δ1 calcium subunit. Injury-induced changes of HVA and LVA ICa are attenuated in TSP4 knockout mice. In the neuropathic pain model of spinal nerve ligation, TSP4 application did not further regulate ICa 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 α2δ1 calcium subunit. Controlling TSP4 overexpression in peripheral sensory neurons may be a target for analgesic drug development for neuropathic pain.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Pan
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Hsiang-En
authors.initials: HE
authors.lastname: Wu
authors.affiliation: Pharmacology, University of California Irvine, Irvine, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Park
authors.affiliation: Departments of Anesthesiology & Perioperative Care and.
authors.forename: Van Nancy
authors.initials: VN
authors.lastname: Trinh
authors.affiliation: Departments of Anesthesiology & Perioperative Care and.|Pharmacology, University of California Irvine, Irvine, CA, USA.
authors.forename: Z David
authors.initials: ZD
authors.lastname: Luo
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Quinn H
authors.initials: QH
authors.lastname: Hogan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002772:Cholera Toxin / Q000378:metabolism; D004195:Disease Models, Animal; D005071:Evoked Potentials / Q000187:drug effects / Q000235:genetics; D005727:Ganglia, Spinal / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D059348:Peripheral Nerve Injuries / Q000235:genetics* / Q000473:pathology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D019699:Thrombospondins / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology
chemical_list: C512066:CACNA2D1 protein, mouse; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D019699:Thrombospondins; C101864:thrombospondin 4; D002772:Cholera Toxin; D002118:Calcium