Hormone Effects on Phosphoinositide Metabolism in Liver

Summary

Vasopressin, epinephrine and angiotensin II markedly stimulated the breakdown of phosphatidylinositol and release of myo-inositol in isolated rat liver cells, but these changes were not significant before 2 min. It is therefore concluded that the degradation of phosphatidylinostol is too slow to account for the increase in cytosolic $C{{a}^{{{{2}^{ + }}}}}$ and activation of phosphorylase caused by these agonists, which occur within 2 s. Breakdown of PIP₂ and release of IP₃ induced by vasopressin and epinephrine occurred more rapidly than the breakdown of phosphatidylinositol, being significant at 3 s with 10⁻⁷ M vasopressin and 10⁻⁵ M epinephrine. The concentration-dependence curves for the effects of vasopressin or epinephrine on PIP₂ breakdown or IP₃ accumulation were not well correlated with those on cytosolic $C{{a}^{{{{2}^{ + }}}}}$ or phosphorylase a. Furthermore, addition of Li⁺ ions enhanced, after 30–60 s, the effects of low concentrations of vasopressin and epinephrine on IP₃ levels, but not on cytosolic $C{{a}^{{{{2}^{ + }}}}}$ or phosphorylase a. These findings may be reconciled with the hypothesis that PIP₂ breakdown and IP₃ release are integrally involved in the effects of vasopressin and epinephrine on cytosolic $C{{a}^{{{{2}^{ + }}}}}$, if it is postulated that an extremely small breakdown of the polyphosphoinositide is sufficient to alter cellular $C{{a}^{{{{2}^{ + }}}}}$ fluxes. In addition, the failure of Li⁺ ions to modify the effects of the agonists on cytosolic Ca²⁺ or phosphorylase could be explained if only those changes in IP₃ that occur within 30–60 s of hormone treatment control cell Ca²⁺ It is concluded that although much more experimentation is required, the bulk of existing evidence supports the hypothesis that PIP₂ breakdown plays a primary role in the actions of Ca²⁺- dependent hormones in liver.