Description:
<jats:p>Ethanol-withdrawal Seizures Are Controlled by Tissue Plasminogen Activator via Modulation of NR2B-containing NMDA Receptors</jats:p><jats:p>Pawlak R, Melchor JP, Matys T, Skrzypiec AE, Strickland S</jats:p><jats:p>Proc Natl Acad Sci USA 2005;102:443–448</jats:p><jats:p>Chronic ethanol abuse causes upregulation of N-methyl-D-aspartate (NMDA) receptors, which underlies seizures and brain damage on ethanol withdrawal (EW). Here we show that tissue plasminogen activator (tPA), a protease implicated in neuronal plasticity and seizures, is induced in the limbic system by chronic ethanol consumption, temporally coinciding with upregulation of NMDA receptors. tPA interacts with NR2B-containing NMDA receptors and is required for upregulation of the NR2B subunit in response to ethanol. As a consequence, tPA-deficient mice have reduced NR2B, extracellular signal-regulated kinase 1/2 phosphorylation, and seizures after EW. tPA-mediated facilitation of EW seizures is abolished by NR2B-specific NMDA antagonist ifenprodil. These results indicate that tPA mediates the development of physical dependence on ethanol by regulating NR2B-containing NMDA receptors.</jats:p><jats:p>Neuroserpin Portland (Ser52Arg) Is Trapped as an Inactive Intermediate That Rapidly Forms Polymers: Implications for the Epilepsy Seen in the Dementia FENIB</jats:p><jats:p>Belorgey D, Sharp LK, Crowther DC, Onda M, Johansson J, Lomas DA</jats:p><jats:p>Eur J Biochem 2004;271:3360–3367</jats:p><jats:p>The dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB), is caused by point mutations in the neuroserpin gene. We have shown a correlation between the predicted effect of the mutation and the number of intracerebral inclusions, and an inverse relation with the age at onset of disease. Our previous work has shown that the intraneuronal inclusions in FENIB result from the sequential interaction between the reactive center loop of one neuroserpin molecule with β-sheet A of the next. We show here that neuroserpin Portland (Ser52Arg), which causes a severe form of FENIB, also forms loop-sheet polymers but at a faster rate, in keeping with the more severe clinical phenotype. The Portland mutant has a normal unfolding transition in urea and a normal melting temperature but is inactive as a proteinase inhibitor. This results in part from the reactive loop being in a less accessible conformation to bind to the target enzyme, tissue plasminogen activator. These results, with those of the CD analysis, are in keeping with the reactive center loop of neuroserpin Portland being partially inserted into β-sheet A to adopt a conformation similar to an intermediate on the polymerization pathway. Our data provide an explanation for the number of inclusions and the severity of dementia in FENIB associated with neuroserpin Portland. Moreover, the inactivity of the mutant may result in uncontrolled activity of tissue plasminogen activator, and so explain the epileptic seizures seen in individuals with more severe forms of the disease.</jats:p>