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¹ Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA

Over the last 10 years we have tried to understand the roles of PIP₂ in regulating cardiac Na⁺–Ca²⁺ exchangers and K_ATP K⁺ channels, both of which are directly activated by PIP₂. Up to now, the idea that hormones might physiologically regulate these mechanisms by causing changes of PIP₂ concentrations in the cardiac sarcolemma, either locally or globally, is not well supported. In intact myocardium, but not excised patches, phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity appears to be Ca²⁺ activated and dependent on cardiac activity. Potentially therefore the primary second messenger of the heart, cytoplasmic Ca²⁺, may regulate PIP₂ and therewith numerous cardiac membrane processes. In general, however, PIP₂ may simply serve to strongly activate various cardiac channels and transporters when they are inserted in the sarcolemma, while a lack of PIP₂ on internal membranes maintains transporters and channels inactive during trafficking and processing. As in most, if not all, strong regulatory systems of cells, the activating effects of PIP₂ can apparently be countered by strong inactivation mechanisms. In this context, our recent work suggests that internalization of cardiac Na⁺–Ca²⁺ exchangers is promoted by increased PIP₂ synthesis, especially in combination with other cell signals. Assuming that multiple adapter–PIP₂ interactions are necessary to initiate the budding of individual membrane vesicles, the dependence of endocytosis on PIP₂ in the surface membrane can potentially be a very steep function. Thus, a better understanding of the regulation of cardiac lipid kinases may be key to understanding when and how cardiac ion transporters and channels are internalized.

(Received 19 March 2007; accepted after revision 20 April 2007; first published online 26 April 2007)
Corresponding author D. W. Hilgemann: Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390-9040, USA. Email: donald.hilgemann{at}utsouthwestern.edu

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