Examination of store-operated Ca(2+) entry (SOC) in single, mechanically skinned skeletal muscle cells by confocal microscopy shows that the inositol 1,4,5-trisphosphate (IP(3)) receptor acts as a sarcoplasmic reticulum [Ca(2+)] sensor and mediates SOC by physical coupling without playing a key role in Ca(2+) release from internal stores, as is the case with various cell types in which SOC was investigated previously. The results have broad implications for understanding the mechanism of SOC that is essential for cell function in general and muscle function in particular. Moreover, the study ascribes an important role to the IP(3) receptors in skeletal muscle, the role of which with respect to Ca(2+) homeostasis was ill defined until now.