RT Journal Article
T1 S-Nitrosylation of Ras Mediates Nitric Oxide-Dependent Post-Injury Neurogenesis in a Seizure Model
A1 Santos, Ana Isabel
A1 Pereira Carreira, Bruno
A1 Izquierdo-Álvarez, Alicia
A1 Ramos, Elena
A1 Lourenço, Ana Sofia
A1 Santos, Daniela Filipa
A1 Morte, Maria Inês
A1 Ribeiro, Luís Filipe
A1 Marreiros, Ana
A1 Sánchez-López, Nuria
A1 Marina, Anabel
A1 Monteiro Carvalho, Caetana
A1 Martínez Ruiz, Antonio
A1 Araújo, Inês Maria
AB Aims: Nitric oxide (NO) is involved in the upregulation of endogenous neurogenesis in the subventricular zone and in the hippocampus after injury. One of the main neurogenic pathways activated by NO is the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway, downstream of the epidermal growth factor receptor. However, the mechanism by which NO stimulates cell proliferation through activation of the ERK/MAPK pathway remains unknown, although p21Ras seems to be one of the earliest targets of NO. Here, we aimed at studying the possible neurogenic action of NO by posttranslational modification of p21Ras as a relevant target for early neurogenic events promoted by NO in neural stem cells (NSCs). Results: We show that NO caused S-nitrosylation (SNO) of p21Ras in Cys118, which triggered downstream activation of the ERK/MAPK pathway and proliferation of NSC. Moreover, in cells overexpressing a mutant Ras in which Cys118 was replaced by a serine–C118S–, cells were insensitive to NO, and no increase in SNO, in ERK phosphorylation, or in cell proliferation was observed. We also show that, after seizures, in the presenceof NO derived from inducible nitric oxide synthase, there was an increase in p21Ras cysteine modification that was concomitant with the previously described stimulation of proliferation in the dentate gyrus.Innovation: Our work identifies p21Ras and its SNO as an early target of NO during signaling events that lead to NSC proliferation and neurogenesis.Conclusion: Our data highlight Ras SNO as an early event leading to NSC proliferation, and they may providea target for NO-induced stimulation of neurogenesis with implications for brain repair
SN 1523-0864
SN 1557-7716
YR 2018
FD 2018-01
LK https://hdl.handle.net/20.500.14352/102924
UL https://hdl.handle.net/20.500.14352/102924
LA eng
NO Foundation for Science and Technology
NO ISCIII, Spanish Government, partially funded by FEDER/ EDRF
DS Docta Complutense
RD 2 sept 2024