Journal of neurochemistry
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Journal of neurochemistry · Sep 2001
Comparative StudyAccumulation of non-erythroid alpha II-spectrin and calpain-cleaved alpha II-spectrin breakdown products in cerebrospinal fluid after traumatic brain injury in rats.
Although a number of increased CSF proteins have been correlated with brain damage and outcome after traumatic brain injury (TBI), a major limitation of currently tested biomarkers is a lack of specificity for defining neuropathological cascades. Identification of surrogate biomarkers that are elevated in CSF in response to brain injury and that offer insight into one or more pathological neurochemical events will provide critical information for appropriate administration of therapeutic compounds for treatment of TBI patients. Non-erythroid alpha II-spectrin is a cytoskeletal protein that is a substrate of both calpain and caspase-3 cysteine proteases. ⋯ Importantly, levels of these proteins were undetectable in CSF of uninjured control rats. These results indicate that detection of alpha II-spectrin and alpha II-SBDPs is a powerful discriminator of outcome and protease activation after TBI. In accord with our previous studies, results also indicate that calpain may be a more important effector of cell death after moderate TBI than caspase-3.
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Journal of neurochemistry · Sep 2001
Distinct signal transduction pathways for GABA-induced GABA(A) receptor down-regulation and uncoupling in neuronal culture: a role for voltage-gated calcium channels.
Changes in GABA receptor (GABA(A)R) gene expression are detected in animal models of epilepsy, anxiety and in post-mortem schizophrenic brain, suggesting a role for GABA(A)R regulation in neurological disorders. Persistent (48 h) exposure of brain neurons in culture to GABA results in down-regulation of GABA(A)R number and uncoupling of GABA and benzodiazepine (BZD) binding sites. Given the central role of GABA(A)Rs in fast inhibitory synaptic transmission, GABA(A)R down-regulation and uncoupling are potentially important mechanisms of regulating neuronal excitability, yet the molecular mechanisms remain unknown. ⋯ Depolarization with 25 mM K(+) produces a sustained increase in intracellular [Ca(2+)] without causing GABA(A)R down-regulation, suggesting that activation of VGCCs is not sufficient to produce GABA(A)R down-regulation. In contrast to GABA(A)R down-regulation, nifedipine and 25 mM K(+) fail to inhibit GABA-induced uncoupling, demonstrating that GABA-induced GABA(A)R down-regulation and uncoupling are mediated by independent molecular events. Therefore, GABA(A)R activation initiates at least two distinct signal transduction pathways, one of which involves elevation of intracellular [Ca(2+)] through VGCCs.