STIM2 Inhibits Intestinal Epithelial Restitution by Repressing STIM1‐Activated Ca 2+ Influx after Wounding

Abstract

TRPC1-mediated Ca2+ signaling is crucial for epithelial restitution, but the exact mechanism underlying TRPC1 regulation remains unknown. We recently show that STIM1 translocation to the plasma membrane (PM) activates TRPC1 channel and enhances restitution by increasing Ca2+ influx. Polyamines also stimulate restitution via STIM1. STIM2 is a homolog of STIM1 and regulates STIM1. This study tested if STIM2 is involved in regulating epithelial restitution via STIM1 and its effect is modulated by polyamines. [Ca2+]cyt, STIM2/STIM1 interaction, and restitution were measured in differentiated IEC cells. STIM2 interacted with and repressed STIM1 activity. Ectopic STIM2 expression prevented STIM1 translocation to PM after wounding, reduced Ca2+ influx, and inhibited cell migration. Polyamine depletion increased endogenous STIM2, which was associated with a repression of restitution. STIM2 silencing enhanced STIM1 abundance in PM and promoted restitution in polyamine-deficient cells. Elevated polyamines by ODC overexpression decreased STIM2 levels and induced STIM1 translocation to PM, thus stimulating restitution. These results indicate that 1) STIM2 down-regulates epithelial restitution by repressing STIM1 translocation to PM and 2) polyamines promote restitution by inhibiting STIM2 expression. Funding: grants from VA (RNJ, JYW) and NIH (JYW).