Antagonistic Regulation of Actin Dynamics and Cell Motility by TRPC5 and TRPC6 Channels

Coupling TRPC5 and TRPC6 calcium channels to different Rho GTPases allows calcium to both promote and inhibit cell migration. Signaling Stop and Go Calcium-dependent remodeling of the actin cytoskeleton through members of the Rho family of small guanosine triphosphatases (Rho GTPases) is crucial for cell migration. Tian et al. investigated the upstream regulation of this process in kidney podocytes, a class of cells associated with glomerular capillaries whose contractile function is crucial to maintenance of the kidney filtration barrier. They found that, although angiotensin II elicited calcium influx through both TRPC5 and TRPC6 (transient receptor potential canonical type 5 and 6) channels, TRPC5 signaled through Rac1 to promote cell motility, whereas TRPC6 signaled through RhoA to inhibit it. Mechanistic analyses indicated that differential activation of the two GTPases depended on their location relative to the two channels: TRPC5 was present in a complex with Rac1 and TRPC6 was associated with RhoA, enabling their antagonistic regulation of the cytoskeleton and thereby their opposing effects on cell migration. The Rho family of small guanosine triphosphatases (Rho GTPases: RhoA, Cdc42, and Rac1) regulates many aspects of cell behavior, including actin dynamics and cell migration. The generation of calcium ion (Ca2+) microdomains is critical in promoting cell migration because they control the localized activity of Rho GTPases. We identified receptor-activated TRPC5 and TRPC6 (transient receptor potential canonical type 5 and 6) channels as antagonistic regulators of actin remodeling and cell motility in fibroblasts and kidney podocytes. We show that TRPC5 is in a molecular complex with Rac1, whereas TRPC6 is in a molecular complex with RhoA. TRPC5-mediated Ca2+ influx induces Rac1 activation, thereby promoting cell migration, whereas TRPC6-mediated Ca2+ influx increases RhoA activity, thereby inhibiting cell migration. Our data unveil antagonistic Ca2+ influx pathways as a conserved signaling mechanism for the integrated regulation of cell migration.

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