title: Chronic interleukin-6 exposure alters metabotropic glutamate receptor-activated calcium signalling in cerebellar Purkinje neurons.
abstract: Chronic central nervous system expression of the cytokine interleukin-6 (IL-6) is thought to contribute to the histopathological, pathophysiological, and cognitive deficits associated with various neurological disorders. However, the effects of chronic IL-6 expression on neuronal function are largely unknown. Previous studies have shown that chronic IL-6 exposure alters intrinsic electrophysiological properties and intracellular Ca2+ signalling evoked by ionotropic glutamate receptor activation in cerebellar Purkinje neurons. In the current study, using primary cultures of rat cerebellum, we investigated the effects of chronic IL-6 exposure on metabotropic glutamate receptor (mGluR)-activated Ca2+ signalling and release from intracellular Ca2+ stores. Chronic exposure (6-10 days) of Purkinje neurons to 500 units/mL IL-6 resulted in elevated resting Ca2+ levels and increased intracellular Ca2+ signals evoked by the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) compared to untreated control neurons. Chronic IL-6 treatment also augmented Ca2+ signals evoked by brief 100 mm K+ depolarization, although to a lesser degree than responses evoked by DHPG. Depleting intracellular Ca2+ stores with sarcoplasmic-endoplasmic reticulum ATPase inhibitors (thapsigargin or cyclopiazonic acid) or blocking ryanodine receptor-dependent release from intracellular stores (using ryanodine) resulted in a greater reduction of DHPG- and K+-evoked Ca2+ signals in chronic IL-6-treated neurons than in control neurons. The present data show that chronic exposure to elevated levels of IL-6, such as occurs in various neurological diseases, alters Ca2+ signalling involving release from intracellular stores. The results support the hypothesis that chronic IL-6 exposure disrupts neuronal function and thereby may contribute to the pathophysiology associated with many neurological diseases.
authors.affiliation: Department of Neuropharmacology, CVN-11, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Nelson
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Netzeband
authors.forename: Donna L
authors.initials: DL
authors.lastname: Gruol
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001927:Brain Diseases / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D011689:Purkinje Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D015850:Interleukin-6; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D019837:Ryanodine Receptor Calcium Release Channel; C079215:3,5-dihydroxyphenylglycine; D000251:Adenosine Triphosphatases; D011188:Potassium; D002118:Calcium; D005998:Glycine