title: Role of calcium in regulation of phosphoinositide signaling pathway.
abstract: Using primary neuronal cultures we have examined the role of extracellular Ca2+ in a receptor-regulated phosphoinositide turnover. We report that receptor (glutamic acid and acetylcholine)-activated phosphoinositide turnover requires the presence of extracellular Ca2+ (EC50 = 21.1 microM). The requirement for Ca2+ appears to be at an intracellular level and is highly selective for Ca2+. We also found that several inorganic and organic Ca2+ channel blockers, including La3+ and verapamil, inhibit phosphoinositide turnover. However, the pharmacological profile of these agents in this regard was distinct from their actions at the voltage-sensitive Ca2+ channels. To explain the above requirement for extracellular Ca2+ in agonist-stimulated phosphoinositide turnover and its sensitivity to Ca(2+)-channel blockers, we propose a hypothetical model suggesting that Ca2+, following IP-3-mediated mobilization, exerts a facilitatory action on the activity of receptor-phospholipase C complex. We further propose that in the absence of extracellular Ca2+ or in the presence of certain Ca(2+)-channel blockers, refilling of calciosomes is ineffectual or inhibited, causing its depletion and subsequent inactivation of agonist-stimulated phosphoinositide turnover.
authors.affiliation: ICI Americas Inc., Wilmington, DE 19897.
authors.forename: J
authors.initials: J
authors.lastname: Patel
authors.forename: R A
authors.initials: RA
authors.lastname: Keith
authors.forename: A I
authors.initials: AI
authors.lastname: Salama
authors.forename: W C
authors.initials: WC
authors.lastname: Moore
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D002413:Cations, Divalent; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism*; D017275:Isradipine; D007700:Kinetics; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D002413:Cations, Divalent; D007295:Inositol Phosphates; D010069:Oxadiazoles; D010716:Phosphatidylinositols; D011810:Quinoxalines; D013449:Sulfonamides; D000001:Calcimycin; D007294:Inositol; D004533:Egtazic Acid; C056723:FG 9041; C017967:W 7; D016318:Quisqualic Acid; D002217:Carbachol; D014700:Verapamil; D004110:Diltiazem; D002118:Calcium; D017275:Isradipine