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The Journal of Neuroscience, March 15, 2003, 23(6):2348

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

Joseph T. Neary¹, Yuan Kang¹, Karen A. Willoughby², and Earl F. Ellis²

¹ Research Service, Veterans Affairs Medical Center, Department of Pathology and Department of Biochemistry and Molecular Biology, and Neuroscience Program, University of Miami School of Medicine, Miami, Florida 33125, and ² Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia 23298

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.

Key words: purinergic receptor; ERK; astrocyte; extracellular ATP; calcium; trauma; brain injury; glia; gliosis; mechanical stretch

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2362348-09$05.00/0

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