Local voltage clamping was applied to mouse macrophage plasma membrane to study calcium channels activated by inositol-1,4,5-triphosphate (IP3) and blocked by heparin. These channels were clearly distinguished from IP3-activated channels of the endoplasmic reticulum by their low conductivity (about 1 pSm for 100 mM Ca2+), high selectivity for Ca2+ relative to K+ (P(Ca):P(K) > 1000), calcium inactivation, and activation on hyperpolarization; these properties allowed them to be assigned to the I(CRAC) family. On the other hand, the properties of the IP3 receptors of these channels (IP3R), i.e., the dose-dependent effect of IP3, the IP3 desensitization of the receptor, and the sensitivity to micromolar concentrations of heparin and arachidonic acid were close to those of the endoplasmic reticulum IP3 receptor. The most likely interpretation of these data is that IP3R are not located in the endoplasmic reticulum, but, acting via some kind of conformational change occurring on binding of IP3, transmit a signal from the endoplasmic reticulum to the highly selective Ca2+ channels. This point of view is in agreement with the published "coupling model" [1].