V. Polyphosphoinositide breakdown as the initiating reaction in receptor-stimulated inositol phospholipid metabolism

All cell-surface receptors that bring about a rise in cytosol Ca²⁺ concentration upon stimulation appear also to provoke enhanced metabolism of inositol phospholipids. For many years, it has been thought that the initiating reaction in this response is phosphodiesterase-catalysed breakdown of phosphatidylinositol(PtdIns). However, recent experiments with hepatocytes, parotid gland and blowfly salivary gland have demonstrated very rapid breakdown of phosphatidyl-inositol-4, 5-bisphosphate (PtdIns4,5P₂), and maybe also of PtdIns4P, in cells stimulated by Ca²⁺-mobilizing stimuli (V₁-vasopressin, anqiotensin, α₁-adrenergic, muscarinic cholinergic, substance P and 5-hydroxytryptamine). As with the disappearance of PtdIns that had been studied previously, this response is not Ca²⁺-mediated and shows a receptor occupation dose-response curve. The PtdIns 'breakdown' studied previously was probably utilization of PtdIns for resynthesis of polyphosphoinositides to replace the degraded PtdIns4,5P₂. We suggest that the primary event in receptor-stimulated inositol phospholipid metabolism is phosphodiesterase attack upon PtdIns4,5P₂ to yield 1,2-diacylglycerol and inositol-1,4,5-triphosphate, and that this is an essential coupling event in a general mechanism by which receptors mobilize Ca²⁺ in the cytosol of stimulated cells.