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Original Article

Phosphatidylinositol-4,5-bisphosphate: Actin Dynamics and the Regulation of ATP-Dependent and -Independent Secretion

Department of Pharmacology, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan

Abstract

It has long been believed that the cortical actin cytoskeleton plays an important role in regulating the secretion of hormones and neurotransmitters. In this study, we investigated the control of actin dynamics in primary neuroendocrine cells and determined the relationship of actin dynamics to various components of the secretory response. The amount of cortical f-actin in chromaffin cells was quantified in confocal images of cells stained with Alexa Fluor 568 phalloidin. Manipulations that decreased levels of phosphatidylinositol-4,5-bisphosphate (PIP₂) (e.g., removal of ATP, the expression of a protein that can sequester PIP₂) rapidly reduced the amount of cortical actin. In contrast, cytoskeletal disruptors such as latrunculin were much less able to reduce cortical actin levels, indicating that the amount of cortical f-actin depends more strongly on PIP₂ than on the availability of g-actin. Not only does PIP₂ regulate actin, but actin regulates the level of PIP₂, as revealed by PIP₂ labeling studies. Manipulation of cortical actin had differing effects on the ATP-dependent and -independent components of secretion. ATP-dependent secretion was particularly sensitive to changes in cortical actin stability and was inhibited by expression of a protein (Yersinia pestis protein kinase A) that disassembles cortical f-actin and by pharmacological agents that promote either disassembly or stabilization of actin. The data suggest that an ATP-dependent component of secretion requires rapid changes in actin dynamics. These results point to a complex web of interactions involving PIP₂, actin, and the secretory response.

Received for publication October 18, 2004.

Accepted for publication January 5, 2005.

Address correspondence to: Dr. Mary A. Bittner, Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, Ann Arbor, MI 48109-0632. E-mail: mbittner{at}umich.edu

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