GENERAL COMMENTARY published: 07 January 2013 doi: 10.3389/fphys.2012.00492 Cholesterol regulation of PIP 2 : why cell type is so important Domenico M. Taglieri 1 , Dawn A. Delfín 2 and Michelle M. Monasky 3 * 1 Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA 2 Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH, USA 3 Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA *Correspondence: monasky@uic.edu Edited by: Steffen-Sebastian Bolz, University of Toronto, Canada Reviewed by: Steffen-Sebastian Bolz, University of Toronto, Canada A commentary on How cholesterol regulates endothelial biomechanics by Hong, Z., Staiculescu, M. C., Hampel, P., Levitan, I., and Forgacs, G. (2012). Front. Physio. 3:426. doi: 10.3389/fphys. 2012.00426 Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) is a phospholipid found in cell membranes, and has been indicated to play important roles in cytoskeletal organization, cell motility, transduction of extracellular signals, regulation of ion channels at the plasma membrane, endocytosis, phagocytosis, and endo- some function. It has also been linked to cancer in humans (Di Paolo and De Camilli, 2006). PIP 2 can be hydrolyzed by membrane-bound phospholipase C beta into two second messengers, IP3 and diacylglycerol (DAG). Plasmalemmal cholesterol has been demonstrated to reg- ulate PIP 2 hydrolysis and thus its cellular function in skin fibroblasts and pancreatic β-cells (Kwik et al., 2003; Hao and Bogan, 2009). In this original research article, Hong et al. (2012) address the role of plasmalem- mal cholesterol in regulating the localiza- tion and metabolism of PIP 2 in endothelial cells and the result on cell stiffness. They suggest that a decrease in cholesterol leads to disruption of PIP 2 hydrolysis, which in turn results in increased cross-links between the membrane and cytoskeleton via PIP 2 and increased cell stiffness. These results are important for understanding certain diseases, such as atherosclerosis, in which cholesterol levels are central to the pathology. The mechanism by which cholesterol regulates PIP 2 in the plasma membrane may not be the same for different cell types. Cholesterol depletion in fibrob- lasts leads to decreased levels of PIP 2 in the plasma membrane, diminished membrane-cytoskeletal attachments, and decreased lateral motility (Kwik et al., 2003). Similarly, in cultured pancreatic β-cells, cholesterol depletion stimulates the hydrolysis of PIP 2 , thus reducing the amount of PIP 2 at the plasma mem- brane (Hao and Bogan, 2009). These find- ings are in contrast to a study using HEK293 cells, in which membrane choles- terol enrichment promoted PIP 2 depletion (Chun et al., 2010). Cholesterol depletion in lymphoblasts results in decreased lat- eral mobility of membrane proteins (Kwik et al., 2003). PIP 2 lateral mobility has been described as low in atrial myocytes, and high in HEK293 cells and fibroblasts (Epand, 2008). Therefore, cholesterol may regulate PIP 2 differently in various cell types. Compartmentalization and regulation of PIP 2 metabolism within the plasma membrane may contribute to differ- ences observed between cell types (Epand, 2008; Kwiatkowska, 2010). Cholesterol- rich membrane microdomains (lipid rafts), which are known to be inti- mately involved in regulating a variety of G-protein coupled receptor-mediated functions, including those regulating PIP 2 metabolism (Allen et al., 2007), have bidirectional relationship with actin cytoskeleton. In response to exter- nal stimuli, G αq/11 subunits stimulate membrane-bound phospholipase C beta, which then cleaves PIP 2 into its two sec- ond messengers. Therefore, it is believed that the relationship among lipid raft- associated PIP 2 , G-proteins, and actin has strong implications in regulating actin assembly to modify cell shape and function. Conversely, actin associates with rafts and caveolae either as polymerized structures or as actin monomers, which might help to organize lipid raft domains and the molecules that are present in this structure to evoke a variety of cell signaling pathways in the cell interior (Caroni, 2001). Another exciting mech- anism involves three proteins, namely GAP43, MARCKS, and CAP23, which accumulate at rafts, where they associate with PIP 2 , and promote its retention and clustering. By modulating PIP 2 at plas- malemmal rafts, GAP43, MARCKS, and CAP23 regulate cell cortex actin dynam- ics through a common mechanism. It is believed that, in response to local signals, these proteins dissociate from PIP 2 , creat- ing local pools of free PIP 2 , which result in diverse intracellular responses. Nonetheless, the mechanisms through which PIP 2 effector molecules medi- ate the various cellular responses to localized liberation of PIP 2 are mostly unknown. Investigations in this direc- tion will foster our understanding of cholesterol-mediated PIP 2 intracellular functions. REFERENCES Allen, J. A., Halverson-Tamboli, R. A., and Rasenick, M. M. (2007). Lipid raft microdomains and neu- rotransmitter signalling. Nat. Rev. Neurosci. 8, 128–140. Caroni, P. (2001). New EMBO members’ review: actin cytoskeleton regulation through mod- ulation of PI(4, 5)P(2) rafts. EMBO J. 20, 4332–4336. Chun, Y. S., Shin, S., Kim, Y., Cho, H., Park, M. K., Kim, T. W., et al. (2010). Cholesterol modu- lates ion channels via down-regulation of phos- phatidylinositol 4,5-bisphosphate. J. Neurochem. 112, 1286–1294. Di Paolo, G., and De Camilli, P. (2006). Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657. www.frontiersin.org January 2013 | Volume 3 | Article 492 | 1