Role of calcium in regulation of phosphoinositide signaling pathway.
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.
Patel
J
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ICI Americas Inc., Wilmington, DE 19897.
Keith
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Salama
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Moore
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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