Activation of the endothelial store-operated ISOC Ca2+ channel requires interaction of protein 4.1 with TRPC4

Store-operated calcium (SOC) entry represents the principal Ca2+ entry pathway into nonexcitable cells. Despite intensive investigation, mechanisms underlying activation of SOC entry have remained elusive. The endothelial I-SOC channel is a Ca2+ selective SOC entry channel to which the transient receptor potential (TRP) proteins TRPC1 and TRPC4 contribute subunits. Activation of I-SOC is specifically regulated by the spectrin-actin membrane skeleton; however, the nature of coupling between the I-SOC channel and membrane skeleton is unknown. Here we demonstrate that protein 4.1 is an essential component of the I-SOC channel gating mechanism. Protein 4.1 interacts with TRPC4 and the membrane skeleton. Deletion of the protein 4.1 binding domain on TRPC4 or peptide competition to the protein 4.1 binding domain prevents I-SOC activation. These findings reveal that interaction of protein 4.1 with TRPC4 is required for activation of the endothelial I-SOC channel.