In most animal cells a decrease in the concentration of Ca2+ in the endoplasmic reticulum (ER) and possibly other intracellular stores results in activation of store-operated Ca2+ channels (SOCs) in the plasma membrane. Physiologically, the empting of Ca2+ stores occurs through inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-operated Ca2+ channels. In addition to being a major component in the mechanism responsible for Ca2+ release from the ER in non-excitable cells, it has been suggested that IP3Rs play a direct role in activation of SOCs by conformational coupling. To elucidate the role of IP3Rs in activation of SOCs in liver, we used short interfering RNA (siRNA) to reduce specifically the expression of the genes encoding each type of IP3R in H4IIE liver cells. Whole cell patch clamping was used to measure the SOC current (ISOC) initiated by the SERCA inhibitor thapsigargin or IP3. Immunofluorescence and Western blotting were employed to verify the effectiveness of siRNA and the time course of the knock down of IP3Rs. We found that all 3 types of IP3Rs are expressed in H4IIE cells, and were able to knock each type down using specific siRNAs. The amplitude of thapsigargin-initiated ISOC in cells transfected with siRNA against each type of IP3R was the same as that in control cells. These results indicate that, in contrast to considerable published data for other cell types, IP3Rs are unlikely to activate SOCs through a conformational coupling mechanism. Using IP3 in the pipette revealed that knocking down IP3 R1, but not the other types of IP3R, is sufficient to prevent activation of the ISOC by IP3. This indicates that Ca2+ stores linked to SOCs predominantly express type 1 IP3R.