Cyclic Phosphatidylinositol Metabolism and Resynthesis

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Hormone-stimulated hydrolysis of phosphatidyl inositol bis- phosphate is followed by conversion of phosphatidyl inositol to phosphatidyl inositol bis-phosphate. Studies indicate that lipid from subcellular organelles in addition to the plasma membrane must be accessible in order to account for the large amount of PtdIns that is often involved in the cycling response. To date, two mechanisms have been proposed to explain this: (1) A PtdIns transfer protein facilitates the transfer of intracellular PtdIns to the plasma membrane, and (2) The bulk of the PtdIns metabolized is hydrolyzed directly, perhaps as a result of the rise in intracellular free calcium, and is not involved in the generation of inositol tris phosphate second messengers or directly associated with a hormone-receptor complex. A third possibility is suggested: (3) Internal membrane PtdIns is accessed as a result of receptor sequestration and recycling through the interior of the cell. A series of experiments have been devised to test this third possibility. They involve inhibition of internalization by potassium depletion as well as by receptor mutation. As a corollary to this hypothesis, compensatory resynthesis of PtdIns need not take place at the plasma membrane. The subcellular location of the PtdIns synthetase enzyme will be determined by immunocytochemistry. %%% One important signaling pathway in the response of cells to hormones involves the breakdown of a membrane component known as phosphatidylinositol bis-phosphate to produce further signal molecules. To maintain a cell's ability to respond to hormone, this material must be resynthesized. The goal of this research is to determine where within the cell resynthesis takes place and how it is controlled in coordination with hormonal stimulation of the cell. The results of this research will contribute important new information on how cells respond to hormones and other external signals.