Differential regulation of the Rac1 GTPase activating protein (GAP) BCR during oxygen/glucose deprivation in hippocampal and cortical neurons [Neurobiology]

Brain ischemia causes oxygen and glucose deprivation (OGD) in neurons, triggering a cascade of events leading to synaptic accumulation of glutamate. Excessive activation of glutamate receptors causes excitotoxicity and delayed cell death in vulnerable neurons. Following global cerebral ischemia, hippocampal CA1 pyramidal neurons are more vulnerable to injury than their cortical counterparts, but the mechanisms that underlie this difference are unclear. Signalling via Rho-family small GTPases, their upstream Guanine nucleotide Exchange Factors (GEFs) and GTPase Activating Proteins (GAPs) is differentially dysregulated in response to OGD/ischemia in hippocampal and cortical neurons. Increased Rac1 activity caused by OGD/ischemia contributes to neuronal death in hippocampal neurons, via diverse effects on NADPH oxidase activity and dendritic spine morphology. The Rac1 GEF Tiam1 mediates an OGD-induced increase in Rac1 activity in hippocampal neurons, however the identity of an antagonistic GAP remains elusive. Here, we show that the Rac1 GAP BCR associates with NMDA receptors (NMDARs) along with Tiam1, and this protein complex is more abundant in hippocampal compared to cortical neurons. While total BCR is similar in the two neuronal types, BCR is more active in hippocampal compared to cortical neurons. OGD causes an NMDAR- and Ca2+- permeable AMPAR-dependent deactivation of BCR in hippocampal, but not cortical neurons. BCR knock-down occludes OGD-induced Rac1 activation in hippocampal neurons. Furthermore, disrupting the Tiam1-NMDAR interaction with a fragment of Tiam1 blocks OGD-induced Tiam1 activation, but has no effect on the deactivation of BCR. This work identifies BCR as a critical player in Rac1 regulation during OGD in hippocampal neurons.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2zjSXs7
via IFTTT