TGF-β-induced Ca²⁺ influx involves the type III IP₃ receptor and regulates actin cytoskeleton

Ca²⁺ influx has been postulated to modulate the signaling pathway of transforming growth factor-β (TGF-β); however, the underlying mechanism and functional significance of TGF-β-induced stimulation of Ca²⁺ influx are unclear. We show here that TGF-β stimulates Ca²⁺ influx in mesangial cells without Ca²⁺ release. The influx of Ca²⁺ is prevented by pharmacological inhibitors of inositol 1,4,5-trisphosphate receptors (IP₃R) as well as specific antibodies to type III IP₃R (IP₃RIII) but not to type I IP₃R (IP₃RI). TGF-β enhances plasma membrane localization of IP₃RIII, whereas the sarcoplasmicendoplasmic reticulum Ca²⁺-ATPase (SERCA) preferentially translocates to the nucleus. Untreated mesangial cells exhibit actin filamentous protrusions on the cell surface, and treatment with TGF-β dramatically reduces this pattern. The alterations in the actin cytoskeleton by TGF-β are dependent on TGF-β-induced Ca²⁺ influx. These studies identify a novel pathway by which TGF-β regulates Ca²⁺ influx and induces cytoskeletal alterations.