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Over the last 10 years we have tried to understand the roles of PIP2 in regulating cardiac Na+–Ca2+ exchangers and KATP 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.