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MBC in Press, published online ahead of print December 12, 2007
Mol. Biol. Cell 10.1091/mbc.E07-07-0713

A more recent version of this article appeared on February 1, 2008
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Submitted on July 28, 2007
Revised on October 25, 2007
Accepted on November 27, 2007

Maintenance of Hormone-sensitive Phosphoinositide Pools in the Plasma Membrane Requires Phosphatidylinositol 4-Kinase III{alpha}

Andras Balla,*{dagger} Yeun Ju Kim,* Peter Varnai,*{dagger} Zsofia Szentpetery,* Zachary Knight,{ddagger} Kevan M. Shokat,{sect} and Tamas Balla*

*Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4510; {dagger}Department of Physiology, Semmelweis University, School of Medicine, Budapest, Hungary; {ddagger}Program in Chemistry and Chemical Biology, University of California, San Francisco, CA 94158; {sect}Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-2140

Monitoring Editor: John York

type III phosphatidylinositol (PtdIns) 4-kinases (PI4Ks) have been previously shown to support plasma membrane phosphoinositide synthesis during phospholipase C activation and Ca2+ signaling. Here we use biochemical and imaging tools to monitor phosphoinositide changes in the plasma membrane in combination with pharmacological and genetic approaches to determine which of the type III PI4Ks ({alpha} or {beta}) is responsible for supplying phosphoinositides during agonist-induced Ca2+ signaling. Using inhibitors that discriminate between the {alpha}- and {beta}-isoforms of type III PI4Ks, PI4KIII{alpha} was found indispensable for the production of PtdIns4P, PtdIns(4,5)P2 and Ca2+ signaling in angiotensin II (AngII) stimulated cells. Down-regulation of either the type II or type III PI4K enzymes by siRNA, had small but significant effects on basal PtdIns4P and PtdIns(4,5)P2 levels in 32P-labeled cells but only PI4KIII{alpha} down-regulation caused a slight impairment of PtdIns4P and PtdIns(4,5)P2 resynthesis in AngII stimulated cells. None of the PI4K siRNA treatments had a measurable effect on AngII induced Ca2+ signaling. These results indicate that a small fraction of the cellular PI4K activity is sufficient to maintain plasma membrane phosphoinositide pools and demonstrate the value of the pharmacological approach in revealing the pivotal role of PI4KIII{alpha} enzyme in maintaining plasma membrane phosphoinositides.

Address correspondence to: Tamas Balla (tambal{at}box-t.nih.gov)




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