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The Journal of Neuroscience, March 9, 2005, 25(10):2557-2565; doi:10.1523/JNEUROSCI.3761-04.2005

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Cellular/Molecular
Plasmalemmal Phosphatidylinositol-4,5-Bisphosphate Level Regulates the Releasable Vesicle Pool Size in Chromaffin Cells

Ira Milosevic,^1,2 Jakob B. Sørensen,¹ Thorsten Lang,² Michael Krauss,³ Gábor Nagy,¹ Volker Haucke,³ Reinhard Jahn,² and Erwin Neher¹

Departments of ¹Membrane Biophysics and ²Neurobiology, Max Planck Institute for Biophysical Chemistry, D-37077 Göttingen, Germany, and ³Institute of Chemistry-Biochemistry, Freie Universität Berlin, D-14195 Berlin, Germany

During exocytosis, certain phospholipids may act as regulators of secretion. Here, we used several independent approaches to perturb the phosphatidylinositol-4,5-bisphosphate [PI(4,5)P₂] level in bovine chromaffin cells to investigate how changes of plasmalemmal PI(4,5)P₂ affect secretion. Membrane levels of PI(4,5)P₂ were estimated by analyzing images of lawns of plasma membranes labeled with fluorescent probes specific for PI(4,5)P₂. The specific PI(4,5)P₂ signal was enriched in submicrometer-sized clusters. In parallel patch-clamp experiments on intact cells, we measured the secretion of catecholamines. Overexpression of phosphatidylinositol-4-phosphate-5-kinase I, or infusion of PI(4,5)P₂ through the patch pipette, increased the PI(4,5)P₂ level in the plasma membrane and potentiated secretion. Expression of a membrane-targeted inositol 5-phosphatase domain of synaptojanin 1 eliminated PI(4,5)P₂ from the membrane and abolished secretion. An inhibitor of phosphatidylinositol-3 kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, led to a transient increase in the PI(4,5)P₂ level that was associated with a potentiation of secretion. After prolonged incubation, the level of PI(4,5)P₂ decreased and secretion was inhibited. Kinetic analysis showed that changes in PI(4,5)P₂ levels led to correlated changes in the size of two releasable vesicle pools, whereas their fusion kinetics remained unaffected. We conclude that during both short- and long-term manipulations of PI(4,5)P₂ level secretion scales with plasma membrane PI(4,5)P₂ content and that PI(4,5)P₂ has an early effect on secretion by regulating the number of vesicles ready for release.

Key words: exocytosis; phosphatidylinositol-4,5-bisphospate; chromaffin cell; phosphatidylinositol 4-phosphate 5-kinase; plasmalemmal microdomains; LY294002

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Received Sep 10, 2004; revised January 24, 2005; accepted January 24, 2005.

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