Abstract
Early rapid mucosal restitution occurs as a consequence of epithelial cell migration to reseal superficial wounds, a process independent of cell proliferation. Our previous studies revealed that the canonical transient receptor potential-1 (TRPC1) functions as a store-operated Ca(2+) channel (SOCs) in intestinal epithelial cells (IECs) and regulates epithelial restitution after wounding, but the exact mechanism underlying TRPC1 activation remains elusive. Caveolin-1 (Cav1) is a major component protein that is associated with caveolar lipid rafts in the plasma membrane and was recently identified as a regulator of store-operated Ca(2+) entry (SOCE). Here, we showed that Cav1 plays an important role in the regulation of mucosal restitution by activating TRPC1-mediated Ca(2+) signaling. Target deletion of Cav1 delayed gastric mucosal repair after exposure to hypertonic NaCl in mice, although it did not affect total levels of TRPC1 protein. In cultured IECs, Cav1 directly interacted with TRPC1 and formed Cav1/TRPC1 complex as measured by immunoprecipitation assays. Cav1 silencing in stable TRPC1-transfected cells by transfection with siCav1 reduced SOCE without effect on the level of resting [Ca(2+)]cyt. Inhibition of Cav1 expression by siCav1 and subsequent decrease in Ca(2+) influx repressed epithelial restitution, as indicated by a decrease in cell migration over the wounded area, whereas stable ectopic overexpression of Cav1 increased Cav1/TRPC1 complex, induced SOCE, and enhanced cell migration after wounding. These results indicate that Cav1 physically interacts with and activates TRPC1, thus stimulating TRPC1-mediated Ca(2+) signaling and rapid mucosal restitution after injury.