Subcellular Organization of Receptor-Mediated Phosphoinositide Turnover*

MUCH of the biochemistry of agonist-induced phosphoinositide metabolism has been elucidated during the past decade; however, less is known concerning the subcellular organization of these biochemical events. Questions remain regarding: 1) the anatomical location of the biochemical reactions involved in the signal transduction events, 2) the relationship between PtdIns-4,5-P2 hydrolysis and resynthesis of phosphatidylinositol (Ptdlns) and 3) the nature of the agonistresponsive phosphoinositide pool and its relationship to the activated receptor complex. In this review, we will outline the information presently available that is relevant to these questions and propose a model that incorporates these data. Studies of a number of biochemical pathways, including those for steroidogenesis, glycolysis, nucleotide biosynthesis, and the urea cycle, suggest a functional association or compartmentation within cells of the enzymes involved (for review, see Ref. 1). Existing data support the thesis that such organization may extend to signal transduction pathways as well. Several lines of evidence suggest that stimulation of the adenylyl cyclase-cAMP signaling pathway leads to cAMP accumulation that occurs in discrete areas of the cell. These include findings that: 1) equivalent increases in the levels of cAMP stimulated by two different agonists do not induce similar effects in either Leydig cells (2) or rat heart (3); 2) there is differential activation of particulate and soluble protein kinases by different agonists (4); and 3) there is differential subcellular localization of cAMP that is dependent on the agonist employed (5). Phosphoinositide cycling (Fig. 1), which is stimulated during signal transduction by agonists that use inositol-l,4,5-trisphosphate and 1,2-diacylglycerol (DAG) as second messenger molecules (for review, see Ref. 6), also displays some properties usually associated with compartmentation. In this manuscript, we will review the evidence that supports functional organization of the agonist-stimulated phosphoinositide cycle, including coupling of resynthesis of phosphatidylinositol (Ptdlns) to hydrolysis of Ptdlns- 4,5-bisphosphate (PtdIns-4,5-P2) and the compartmentation of the phosphoinositides into agonist-responsive and -unresponsive pools. A third piece of compelling evidence supporting the compartmentation hypothesis is the spatial aspect of the calcium mobilization response to different agonists. These data have been reviewed elsewhere (7) and will not be discussed here.