Activation of Extracellular Signal-Regulated Kinase by Stretch-Induced Injury in Astrocytes Involves Extracellular ATP and P2 Purinergic Receptors

Abstract

Gliosis is characterized by hypertrophic and hyperplastic responses of astrocytes to brain injury. To determine whether injury of astrocytes produced by an in vitro model of brain trauma activates extracellular signal-regulated protein kinase (ERK), a key regulator of cellular proliferation and differentiation, astrocytes cultured on deformable SILASTIC membranes were subjected to rapid, reversible strain (stretch)-induced injury. Activation of ERK was observed 1 min after injury, was maximal from 10 to 30 min, and remained elevated for 3 hr. Activation of ERK was dependent on the rate and magnitude of injury; maximum ERK activation was observed after a 20-60 msec, 7.5 mm membrane displacement. ERK activation was blocked by inhibiting MEK, the upstream activator of ERK. Activation of ERK was reduced when calcium influx was diminished. When extracellular ATP was hydrolyzed by apyrase or ATP/P2 receptors were blocked, injury-induced ERK activation was significantly reduced. P2 receptor antagonist studies indicated a role for P2X2 and P2Y1, but not P2X1, P2X3, or P2X7, receptors in injury-induced ERK activation. These findings demonstrate for the first time that ATP released by mechanical injury is one of the signals that triggers ERK activation and suggest a role for extracellular ATP, P2 purinergic receptors, and calcium-dependent ERK signaling in the astrocytic response to brain trauma.

Effects of P2Y1 receptor on glial fibrillary acidic protein and glial cell line-derived neurotrophic factor production of astrocytes under ischemic condition and the related signaling pathways

“…ADP evokes an increase in the PI3-K activity and blocking of the P2Y 1 receptor by MRS2179 additionally increases this ADP response. These results suggest that the P2Y 1 receptor has an inhibitory effect on PI3-K signaling pathway [25] . In our study, we found that blockage of P2Y 1 receptor could increase the production of GDNF.…”

“…Inhibition of ERK signaling blocks phosphorylation of Ser727-STAT3, and inhibition of STAT3 activation prevents ATP-stimulated mitogenesis [7] . ATP released by injuried astrocytes activates ERK through P2X 2 and P2Y 1 [25] . ADP can activate ERK1/ERK2 through P2Y 1 and P2Y 12 which leads to cell proliferation of cultured glioma C6 cells [26] .…”

Shock Wave Treatment Enhances Cell Proliferation and Improves Wound Healing by ATP Release-coupled Extracellular Signal-regulated Kinase (ERK) Activation

“…In addition to Erk1/2 and p38 MAPK, the downstream signaling mechanisms triggered by shock wave-induced P2 receptor activation may also involve additional signaling intermediates such as Ras and hypoxiainducible factor 1a transactivation (20,23). A study dealing with stretch-induced injury reported the activation of Erk1/2 to be dependent on the rate and amplitude of mechanical impact, involving released ATP and activated P2 receptors (46). Akt and mammalian target of rapamycin signaling pathways are known as essential regulators of cell proliferation (50 -52).…”

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

“…20,57 ATP released by astrocytes activates AKT and ERK signaling, resulting in gliosis following traumatic brain injury. 58,59 Injury-triggered extracellular ATP also affects microglial response following brain injury. 60,61 We have identified that injury-triggered lysosome exocytosis causes secretion of acid sphingomyelinase (ASM), which is needed for cell membrane repair.…”