title: Interleukin-1 beta enhances endocytosis of glial glutamate transporters in the spinal dorsal horn through activating protein kinase C.
abstract: Excessive activation of glutamate receptors in spinal dorsal horn neurons is a key mechanism leading to abnormal neuronal activation in pathological pain conditions. Previous studies have shown that activation of glutamate receptors in the spinal dorsal horn is enhanced by impaired glial glutamate transporter functions and proinflammatory cytokines including interleukin-1 beta (IL-1β). In this study, we for the first time revealed that spinal glial glutamate transporter activities in the neuropathic animals are attenuated by endogenous IL-1β. Specifically, we demonstrated that nerve injury results in an increased expression of IL-1β and activation of PKC in the spinal dorsal horn as well as suppression of glial glutamate uptake activities. We provided evidence that the nerve-injury induced suppression of glial glutamate uptake is at least in part ascribed to endogenous IL-1β and activation of PKC in the spinal dorsal horn. IL-1β reduces glial glutamate transporter activities through enhancing the endocytosis of both GLT-1 and GLAST glial glutamate transporters. The IL-1β induced trafficking of glial glutamate transporters is through the calcium/PKC signaling pathway, and the dynamin-dependent endocytosis, which is dependent on the integrity of actin filaments. The signaling pathway regulating glial glutamate transporters revealed in this study provides novel targets to attenuate aberrant activation of glutamate receptors in the spinal dorsal horn, which could ultimately help the development of analgesics.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia; Department of Cardiovascular Medicine, The Third Hospital of Wuhan, Wuhan, Hubei Province, China.
authors.forename: Xisheng
authors.initials: X
authors.lastname: Yan
authors.forename: Ruchi
authors.initials: R
authors.lastname: Yadav
authors.forename: Mei
authors.initials: M
authors.lastname: Gao
authors.forename: Han-Rong
authors.initials: HR
authors.lastname: Weng
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D009457:Neuroglia / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D066148:Spinal Cord Dorsal Horn / Q000503:physiopathology*; D013127:Spinal Nerves / Q000293:injuries
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C587672:IL1B protein, mouse; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; C493395:Slc1a2 protein, rat; C493392:Slc1a3 protein, rat; D011493:Protein Kinase C; D034281:Dynamins; D002118:Calcium
keywords: GLT-1; calcium imaging; glutamate transporter current; nociception