Cells can respond to extracellular stimuli with an increase in the concentration of free intracellular Ca2+ in a spatio-temporally controlled manner. Inositol 1,4,5-trisphosphate (InsP3), which stimulates release of Ca2+ from the endoplasmic reticulum (ER), provides a link between receptors at the plasma membrane and cytoplasmic Ca2+ signals. Cyclic AMP (cAMP) sensitises InsP3 receptors (InsP3Rs) to InsP3. As shown previously by the authors, it binds either directly to the InsP3R or to a protein that is tightly associated with it. In this study (p. 2305), Stephen Tovey and Colin Taylor investigate the InsP3-evoked release of Ca2+ at lipid rafts, which are known important sites of Ca2+ signalling. Using an InsP3 biosensor that allows the recording of InsP3 levels in real time, they find that within a cell there are distinct pools of M3-type muscarinic acetylcholine receptors (M3Rs) at the cell surface, which generate different types of InsP3 signals. M3Rs in lipid rafts deliver InsP3 at a high concentration to associated InsP3Rs, stimulating them to release Ca2+, whereas those outside rafts are less closely associated with InsP3Rs. M3Rs outside rafts provide insufficient local InsP3 to activate InsP3Rs directly, and instead InsP3Rs require sensitisation by cAMP. This communication between M3Rs and InsP3Rs might provide specificity to the ubiquitous messenger InsP3, which is controlled further by cAMP regulating the sensitivity of its receptor.