Rac/Rho pathway regulates actin depolymerization induced by aminoglycoside antibiotics.
Stress stimuli can lead to remodeling of the actin cytoskeleton and subsequent alteration of cell adhesion and permeation as well as cell functions and cell fate. We investigated redox-dependent Rho GTPase-linked pathways controlling the actin cytoskeleton in the inner ear of the CBA mouse, by using aminoglycoside antibiotics as a noxious stimulus that causes loss of sensory cells via the formation of reactive oxygen species. Kanamycin treatment in vivo interfered with the formation of F-actin, disturbed the arrangement of beta-actin in the stereocilia of outer hair cells, and altered the intermittent adherens junction/tight junction complexes between outer hair cells and supporting cells. The drug treatment also activated Rac1 and promoted the formation of the complex of Rac1 and p67phox while decreasing the activity of RhoA and reducing the formation of the RhoA/p140mDia complex. In inner-ear-derived cell lines, expression of mutated Rac1 changed the structural arrangement of F-actin and diminished the immunoreactivity of p140mDia. These findings suggest that actin depolymerization induced by kanamycin is mediated by Rac1 activation, followed by the formation of superoxide by NADPH oxidase. These changes will ultimately contribute to aminoglycoside-induced loss of hair cells.
Jiang
Hongyan
H
Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor, Michigan, USA.
Sha
Su-Hua
SH
Schacht
Jochen
J
D000199:Actins / Q000187:drug effects / Q000378:metabolism*; D000617:Aminoglycosides / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000080865:Formins; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007612:Kanamycin / Q000633:toxicity; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D011108:Polymers / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism
D000199:Actins; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; C491464:Diap1 protein, mouse; D000080865:Formins; D010750:Phosphoproteins; D011108:Polymers; D017382:Reactive Oxygen Species; C079789:neutrophil cytosol factor 67K; D013481:Superoxides; D007612:Kanamycin; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein