Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels.
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 (Ca(2+)) 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 Ca(2+) influx induces Rac1 activation, thereby promoting cell migration, whereas TRPC6-mediated Ca(2+) influx increases RhoA activity, thereby inhibiting cell migration. Our data unveil antagonistic Ca(2+) influx pathways as a conserved signaling mechanism for the integrated regulation of cell migration.
Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
Dequan
D
Tian
Sarah M P
SM
Jacobo
David
D
Billing
Anete
A
Rozkalne
Steven D
SD
Gage
Theodora
T
Anagnostou
Hermann
H
Pavenstädt
Hermann
H
Pavenstaedt
Hsiang-Hao
HH
Hsu
Johannes
J
Schlondorff
Arnolt
A
Ramos
Anna
A
Greka
D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D000199:Actins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C112021:Trpc5 protein, mouse; C492146:Trpc6 protein, mouse; C526380:RhoA protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D002118:Calcium