The Journal of neuroscience : the official journal of the Society for Neuroscience
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Bcl-2 family gene products are critical to the integration of cell death stimuli that target the mitochondrion. Proapoptotic BAD (Bcl-2-associated death protein) has been shown to dissociate from its sequestered site with the molecular chaperone protein 14-3-3 and displace proapoptotic BAX (Bcl-2-associated X protein) from antiapoptotic BCL-Xl. BAX subsequently translocates to the mitochondrion and induces cytochrome c release and caspase activation. ⋯ In contrast, the primarily uninjured cortex exhibited increased phosphorylation of Akt (protein kinase B), which may phosphorylate and inhibit BAD, and no altered binding of BAD to BCL-Xl. Finally, administration of an inhibitor of phosphatidylinositol 3-kinase (LY294002), thought to be an upstream activator of Akt, exacerbated cortical apoptosis after seizures. These data suggest that seizures elicit divergent cell death and survival responses within neuronal populations and that the BAD cell death pathway may perform an instigator or reinforcement role in seizure-induced neuronal death.
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The Rho family of small GTPases, key regulators of the actin cytoskeleton in eukaryotic cells from yeast to human, is implicated in the control of neuronal morphology. Guanine nucleotide exchange factors (GEFs) are upstream positive regulators of Rho GTPases and integrate extracellular signaling for appropriate activation of Rho GTPases at specific subcellular regions. Here we describe the identification of a novel Dbl family GEF for Rho GTPases in Homo sapiens and Mus musculus. ⋯ FIR was found to activate the biochemical pathway specific for Rac1 but not for RhoA or Cdc42. Ectopic expression of FIR in the cortical neurons resulted in significantly shortened neurites and excessive growth cones, presumably mediated by Rac1. These results suggest that FIR may regulate neurite remodeling by mediating the signaling pathways from membrane proteins to Rac.
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GABA(A) receptors are allosteric ligand-gated ion channels. Agonist-induced gating and desensitization have been proposed to be coupled via pore domain structures. Mutations at two alpha1 subunit pore-domain (transmembrane domain 2) residues enhance GABA sensitivity, leucine-to-threonine at position 264 (9'), and serine-to-isoleucine at position 270 (15'). ⋯ These results indicate that both alpha1(L264T) and alpha1(S270I) mutations increase the gating efficacy of receptors by slowing channel closing, which accounts for nearly all of the similar changes that they produce in macrocurrent dynamics. Because the alpha1(S270I) mutation uncouples its gating effects from those on rapid desensitization, these two processes are necessarily associated with movements of distinct receptor structures (gates). The effects of the alpha1(L264T) mutation suggest that the conserved leucines may play a role in gating-desensitization coupling.