title: A fundamental role for the nitric oxide-G-kinase signaling pathway in mediating intercellular Ca(2+) waves in glia.
abstract: In this study, we highlight a role for the nitric oxide-cGMP-dependent protein kinase (NO-G-kinase) signaling pathway in glial intercellular Ca(2+) wave initiation and propagation. Addition of the NO donor molsidomine (100-500 microM) or puffing aqueous NO onto primary glial cell cultures evoked an increase in [Ca(2+)](i) in individual cells and also local intercellular Ca(2+) waves, which persisted after removal of extracellular Ca(2+). High concentrations of ryanodine (100-200 microM) and antagonists of the NO-G-kinase signaling pathway essentially abrogated the NO-induced increase in [Ca(2+)](i), indicating that NO mobilizes Ca(2+) from a ryanodine receptor-linked store, via the NO-G-kinase signaling pathway. Addition of 10 microM nicardipine to cells resulted in a slowing of the molsidomine-induced rise in [Ca(2+)](i), and inhibition of Mn(2+) quench of cytosolic fura-2 fluorescence mediated by a bolus application of 2 microM aqueous NO to cells, indicating that NO also induces Ca(2+) influx in glia. Mechanical stress of individual glial cells resulted in an increase in intracellular NO in target and neighboring cells and intercellular Ca(2+) waves, which were NO, cGMP, and G-kinase dependent, because incubating cells with nitric oxide synthase, guanylate cyclase, and G-kinase inhibitors, or NO scavengers, reduced Delta[Ca(2+)](i) and the rate of Ca(2+) wave propagation in these cultures. Results from this study suggest that NO-G-kinase signaling is coupled to Ca(2+) mobilization and influx in glial cells and that this pathway plays a fundamental role in the generation and propagation of intercellular Ca(2+) waves in glia.
authors.affiliation: Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF. spjnnjw@iop.kcl.ac.uk
authors.forename: N J
authors.initials: NJ
authors.lastname: Willmott
authors.forename: K
authors.initials: K
authors.lastname: Wong
authors.forename: A J
authors.initials: AJ
authors.lastname: Strong
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001081:Apyrase / Q000494:pharmacology; D001253:Astrocytes / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D009474:Neurons / Q000166:cytology; D009529:Nicardipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D029742:Caenorhabditis elegans Proteins; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D004963:Estrenes; D016166:Free Radical Scavengers; D007093:Imidazoles; D007476:Ionophores; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D019837:Ryanodine Receptor Calcium Release Channel; D013873:Thionucleotides; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D012433:Ryanodine; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D004533:Egtazic Acid; D015759:Ionomycin; D013498:Suramin; D011189:Potassium Chloride; C041715:6-anilino-5,8-quinolinedione; D009529:Nicardipine; D019001:Nitric Oxide Synthase; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D001081:Apyrase; D006152:Cyclic GMP; D002118:Calcium