AGONIST-SELECTIVE REGULATION OF POLYPHOSPHOINOSITIDE METABOLISM IN PULMONARY-ARTERY SMOOTH-MUSCLE CELLS

Using a rat pulmonary artery smooth muscle cell line (PAC1), detailed analysis of polyphosphoinositide (PPI) metabolism reveals receptor typ e-selective patterns in the formation of inositol phosphates and and 3 -hydroxy-phosphorylated PPIs. Responses to several agonists that stimu late hypertrophy or proliferation were examined, and distinct categori es of response profile were observed. Thrombin and angiotensin II stim ulated the hydrolysis of phosphatidylinositol (PI) 4,5-bisphosphate an d the formation of several cytosolic species of inositol phosphates wi thout the activation of PI 3-hydroxykinase. The response to thrombin w as distinctive because a very large production of inositol 1,4-bisphos phate was accompanied by hydrolysis of PI 4 phosphate. The response to platelet-derived growth factor (PDGF) was distinguished by the produc tion of the PI 3-hydroxykinase product, PI 3,4,5-trisphosphate, and th e appearance of PI 3-hydroxykinase activity in immunoprecipitates. PDG F treatment of PAC1 cultures did not produce accumulation of detectabl e amounts of inositol 1,4,5-trisphosphate, although a small sustained elevation in the level of inositol monophosphate and a gradual accumul ation of inositol 1,3,4 trisphosphate were observed. Characterization of these distinctive responses permitted us to correlate agonist-regul ated PPI metabolism with induction of immediate-early genes and stimul ation of hypertrophy or proliferation of PAC1 cultures (Rothman, A., W olner, B., Button, D., and Taylor, P. (1994) J. Biol. Chem. 269, 6399- 6404). Thrombin-stimulated PPI turnover and the production of a high l evel of inositol bisphosphate may be early signals linked to the induc tion of fosB and PAC1 cell hypertrophy, whereas the activation of PI 5 -hydroxykinase and the accumulation of PI 3,4,5-trisphosphate in respo nse to PDGF appear to be associated with mitogenesis.