Microdomains such as rafts are considered as scaffolds for phosphatidylinositol (4,5) bisphosphate (PIP2) signaling, enabling PIP2 to selectively regulate different processes in the cell. Enrichment of PIP2 in microdomains was based on cholesterol-depletion and detergent-extraction studies. Here we show that two distinct phospholipase C-coupled receptors (those for neurokinin A and endothelin) share the same, homogeneously distributed PIP2 pool at the plasma membrane, even though the neurokinin A receptor is localized to microdomains and is cholesterol dependent in its PIP2 signaling whereas the endothelin receptor is not. Our experiments further indicate that detergent treatment causes PIP2 clustering and that cholesterol depletion interferes with basal, ligand-independent recycling of the neurokinin A receptor, thereby providing alternative explanations for the enrichment of PIP2 in detergent-insoluble membrane fractions and for the cholesterol dependency of PIP2 breakdown, respectively.