Protein kinase signaling cascades in CNS trauma

Abstract

SummaryAdvances in our understanding of the signaling pathways and cellular functions regulated by protein kinase cascades have paved the way to study their role in the response of brain and spinal cord to traumatic injury. Mechanical forces imparted by trauma stimulate mitogen-activated protein kinases and protein kinase B/Akt as well as cause changes in the state of phosphorylation of glycogen synthase kinase-3b. Extracellular ATP released by mechanical strain stimulates P2 purinergic receptors that are coupled to these protein kinase signaling pathways. These kinases regulate gene expression, cell survival, proliferation, differentiation, growth arrest, and apoptosis, thereby affecting cell fate, repair and plasticity after trauma. Elucidation of the molecular responses of protein kinase cascades to mechanical strain and the genes regulated by these signaling pathways may lead to therapeutic opportunities to minimize losses in motor skills and cognitive function caused by trauma to the central nervous system. IUBMB Life, 57: 711 -718, 2005

Phosphorylation mechanisms in intensive care medicine

“…TBI is specifically linked to many phosphorylation pathways; however, MAPKs, PI3K/Akt, and GSK seem to play a dominant role in this pathogenesis [58]. In terms of MAPKs, in vivo models of TBI show that ERK phosphorylation is consistently activated, while p38 and JNK vary depending on the injury [33].…”

“…4 The role of phosphoinositide-3 kinase isoforms in various aspects of critical illness, highlighting the major role of some dominant downstream intracellular signaling molecules occurred in the cortex and hippocampus within 10 min [19], while activation in the parietal and occipital cortexes was seen after 7 days [24]. Moreover, TBI-induced ERK phosphorylation occurs early in neurons, but later in astrocytes and the hippocampus [58]. Furthermore, while most studies agree that TBI increases ERK phosphorylation, many debate whether this has detrimental or beneficial affects, since ERK inhibition can decrease cortical lesion size and atrophy [56], but its inhibition impairs memory and motor skills following TBI [19].…”

“…Furthermore, while most studies agree that TBI increases ERK phosphorylation, many debate whether this has detrimental or beneficial affects, since ERK inhibition can decrease cortical lesion size and atrophy [56], but its inhibition impairs memory and motor skills following TBI [19]. The temporal nature may, in fact, determine its positive or negative role, where early activation is detrimental as it induces premature neurite outgrowth, while late activation can increase plasticity and synaptic formation [58].…”

“…Phosphorylation of GSK-3b is also believed to contribute to TBI [58], since unilateral hemisection of the spinal cord and lithium inhibition of GSK-3b enhanced regeneration of neurons and significantly improved recovery of forelimb function [85]. No clinical trials have attempted to target phosphorylation during TBI, partly due to the reservations that TBI lacks an appropriate therapeutic window; however, in vivo studies show that injury may be worsened by sustained kinase activation, while other phosphorylation events may assist in neuronal repair [58].…”

“…No clinical trials have attempted to target phosphorylation during TBI, partly due to the reservations that TBI lacks an appropriate therapeutic window; however, in vivo studies show that injury may be worsened by sustained kinase activation, while other phosphorylation events may assist in neuronal repair [58].…”