Park, John, Yu, Yanhui Peter, Zhou, Chun-Yi, Li, Kang-Wu, Wang, Dongqing, Chang, Eric, Kim, Doo-Sik, Vo, Benjamin, Zhang, Xia, Gong, Nian, Sharp, Kelli, Steward, Oswald, Vitko, Iuliia, Perez-Reyes, Edward, Eroglu, Cagla ORCID: 0000-0002-7204-0218, Barres, Ben, Zaucke, Frank, Feng, Guoping and Luo, Z. David (2016). Central Mechanisms Mediating Thrombospondin-4-induced Pain States. J. Biol. Chem., 291 (25). S. 13335 - 13349. ROCKVILLE: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. ISSN 1083-351X

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Abstract

Peripheral nerve injury induces increased expression of thrombospondin-4 (TSP4) in spinal cord and dorsal root ganglia that contributes to neuropathic pain states through unknown mechanisms. Here, we test the hypothesis that TSP4 activates its receptor, the voltage-gated calcium channel Ca-v alpha(2)delta(1) subunit (Ca-v alpha(2)delta(1)), on sensory afferent terminals in dorsal spinal cord to promote excitatory synaptogenesis and central sensitization that contribute to neuropathic pain states. We show that there is a direct molecular interaction between TSP4 and Ca-v alpha(2)delta(1) in the spinal cord in vivo and that TSP4/Ca-v alpha(2)delta(1)-dependent processes lead to increased behavioral sensitivities to stimuli. In dorsal spinal cord, TSP4/Ca-v alpha(2)delta(1)-dependent processes lead to increased frequency of miniature and amplitude of evoked excitatory post-synaptic currents in second-order neurons as well as increased VGlut(2)- and PSD95-positive puncta, indicative of increased excitatory synapses. Blockade of TSP4/Ca-v alpha(2)delta(1)-dependent processes with Ca-v alpha(2)delta(1) ligand gabapentin or genetic Ca-v alpha(2)delta(1) knockdown blocks TSP4 induced nociception and its pathological correlates. Conversely, TSP4 antibodies or genetic ablation blocks nociception and changes in synaptic transmission in mice overexpressing Ca-v alpha(2)delta(1). Importantly, TSP4/Ca-v alpha(2)delta(1)-dependent processes also lead to similar behavioral and pathological changes in a neuropathic pain model of peripheral nerve injury. Thus, a TSP4/Ca-v alpha(2)delta(1)-dependent pathway activated by TSP4 or peripheral nerve injury promotes exaggerated presynaptic excitatory input and evoked sensory neuron hyperexcitability and excitatory synaptogenesis, which together lead to central sensitization and pain state development.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Park, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yu, Yanhui PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhou, Chun-YiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, Kang-WuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, DongqingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chang, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, Doo-SikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vo, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, XiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gong, NianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sharp, KelliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steward, OswaldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vitko, IuliiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez-Reyes, EdwardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eroglu, CaglaUNSPECIFIEDorcid.org/0000-0002-7204-0218UNSPECIFIED
Barres, BenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zaucke, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feng, GuopingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luo, Z. DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-272136
DOI: 10.1074/jbc.M116.723478
Journal or Publication Title: J. Biol. Chem.
Volume: 291
Number: 25
Page Range: S. 13335 - 13349
Date: 2016
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Place of Publication: ROCKVILLE
ISSN: 1083-351X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BIOSPECIFIC INTERACTION ANALYSIS; CHANNEL ALPHA(2)DELTA SUBUNITS; SURFACE-PLASMON RESONANCE; GATED CALCIUM-CHANNELS; NEUROPATHIC PAIN; SPINAL-CORD; UP-REGULATION; PERIPHERAL NEUROPATHY; GABAPENTIN NEURONTIN; DOUBLE-BLINDMultiple languages
Biochemistry & Molecular BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27213

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