Faculty Collaboration Database

Increased thrombospondin-4 after nerve injury mediates disruption of intracellular calcium signaling in primary sensory neurons. Neuropharmacology 2017 May 01;117:292-304

Date

02/25/2017

Pubmed ID

28232180

Pubmed Central ID

PMC5414309

DOI

10.1016/j.neuropharm.2017.02.019

Scopus ID

2-s2.0-85013849482 (requires institutional sign-in at Scopus site)   16 Citations

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 (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.

Author List

Guo Y, Zhang Z, Wu HE, Luo ZD, Hogan QH, Pan B

Author

Quinn H. Hogan MD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Calcium
Calcium Channels
Calcium Signaling
Cytoplasm
Disease Models, Animal
Endoplasmic Reticulum
Female
Ganglia, Spinal
Male
Membrane Potentials
Mice, 129 Strain
Mice, Knockout
Neuralgia
Plasma Membrane Calcium-Transporting ATPases
Protein Kinase C
Rats, Sprague-Dawley
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Sensory Receptor Cells
Spinal Nerves
Thrombospondins