Group I metabotropic receptor antagonism blocks depletion of calcium stores and reduces potentiated capacitative calcium entry in strain-injured neurons and astrocytes.

摘要

Antagonism of the group I metabotropic receptor subtype 1 (mGluR1) with (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) has been shown to reduce deficits after in vivo or in vitro traumatic brain injury. We have previously demonstrated that AIDA prevents elevation of astrocyte IP3 subsequent to injury-induced activation of mGluRs and phospholipase C. Since IP3 can cause release of intracellular Ca2+ stores we tested the hypothesis that pre- or post-injury treatment with AIDA can affect (1) the depletion of Ca2+ stores which occurs soon after strain injury of cultured neurons and astrocytes and (2) the delayed potentiation of capacitative calcium entry in strain-injured neurons. Astrocyte or neuronal plus glial cultures were grown on Silastic membranes that were subjected to a 50-msec pulse of compressed gas, which caused membrane displacement and biaxial strain (stretch) injury of the adhering cells. Cells were treated 10 min before or immediately after injury with 100 microM AIDA and the intracellular free Ca2+ ([Ca2+]i) response to thapsigargin, which inhibits the ability of the stores to sequester Ca2+, was measured at 15 min or 3 h after injury. AIDA pre- or post-injury treatment prevented the depletion of intracellular calcium stores at 15 min post-injury in astrocytes and neurons and reduced the potentiated neuronal capacitative calcium influx 3 h after injury. Since Ca2+ and Ca2+ stores influence many factors, including neuronal excitability, plasticity, protein synthesis, and neuronal-glial interactions, prevention of Ca2+ store depletion and subsequent exaggerated capacitative calcium entry may be an important subcellular mechanism by which antagonism of mGluR1 receptors exert an injury-reducing effect. More globally, the results further emphasize the importance of altered signaling and calcium regulatory mechanisms in the immediate and delayed sequelae of traumatic brain injury.