Synaptic versus extrasynaptic NMDA receptor signaling: CREB makes the difference

Synaptic versus extrasynaptic NMDA receptor signaling: CREB makes the difference

News & Comment TRENDS in Pharmacological Sciences Vol.23 No.7 July 2002 305 Journal Club Synaptic versus extrasynaptic NMDA receptor signaling: CR...

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News & Comment

TRENDS in Pharmacological Sciences Vol.23 No.7 July 2002


Journal Club

Synaptic versus extrasynaptic NMDA receptor signaling: CREB makes the difference The NMDA receptor plays a key role during neuronal development and the induction of various forms of synaptic plasticity in the CNS, including long-term potentiation and long-term depression. However, prolonged activation of the same receptor under pathological conditions such as cerebral ischemia and traumatic injury causes neuronal cell death. What is the stimulus that triggers such a different cellular consequence? The NMDA receptor is highly permeable to Ca2+ ions and it has been suggested that different sites and kinetics of Ca2+ entry have an important role in triggering the two processes. Previous work demonstrated that Ca2+ entry through L-type Ca2+ channels promotes cell survival via the expression of CREB (cAMP response element-binding protein)-activated genes such as the gene encoding BDNF (brainderived neurotrophic factor). By contrast, the exogenous application of glutamate inhibits CREB-dependent gene transcription and is neurotoxic to cells. Now, Hardingham et al. [1] have shed light on the dual nature of NMDA receptor

signaling (i.e. synaptic versus extrasynaptic NMDA receptor activation). The authors were able to dissect, in cultured hippocampal neurons, the contribution of the extrasynaptic receptor from that of the synaptic receptor by using an experimental protocol that selectively wiped out the synaptic component. In this way they found that activation of NMDA receptors by synaptic activity mediates CREB-dependent BDNF expression, trkB receptor phosphorylation and protection from staurosporin-induced apoptosis. By contrast, stimulation of extrasynaptic receptors by glutamate initiated a CREB-mediated dephosphorylation pathway, blocked the induction of BDNF expression and led to mitochondrial dysfunction and cell death. Thus, signaling through extrasynaptic NMDA receptor activation prevents the pro-survival pathways derived from synaptic NMDA receptor activation. Ifenprodil, a selective antagonist of the NR2B subunit of the NMDA receptor, can completely block the CREB-mediated shut-off pathway activated by extrasynaptic

NMDA receptors, which suggests that distinct subunit compositions of the receptors mediate the two opposing effects. The authors provide evidence that differences in the location of the activated receptors are functionally important: stimulation of synaptic NMDA receptors leads to cell survival whereas extrasynaptic NMDA receptors mediate neuronal death. Because high concentrations of activated CREB and increases in BDNF expression were observed in surviving neurons following ipoxic–ischemic episodes, pharmacological tools that selectively potentiate synaptic NMDA receptor activation but block extrasynaptic NMDA receptor activation could be useful in decreasing or preventing neuronal damage during pathological states. 1 Hardingham, G.E. et al. (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414

Giulia Puja [email protected]

Rapidly acting steroids? Corticosteroids represent one of the most widely used and effective therapeutic interventions available to modern medical practice. A glance at any medical textbook reveals that the range of clinical conditions for which corticosteroids are regularly and effectively used is both extensive and diverse, encompassing many inflammatory, allergic, immune and other disorders, including eczema, rheumatoid arthritis, asthma, Crohn’s disease and cancer, to name but a few. This impressive list shows no sign of shrinking despite the well-recognized and significant drawbacks associated with steroid usage, particularly in the long-term. A literal pot of gold surely awaits the pharmaceutical alchemist who can develop a drug with the efficacy of a steroid but without the accompanying side-effects. One of the more mysterious indications for steroid therapy, however, is for cardiovascular and septic shock. The mystery

arises because steroids exert their pharmacological effects by altering gene transcription, a process that takes a matter of hours, whereas the supposed beneficial effects of acutely administered large doses of steroids such as dexamethasone are apparent almost instantaneously, and certainly within a time frame that precludes significant modifications of gene expression. Although corticosteroids are not now widely used for these indications because of the frequency and severity of adverse events, nevertheless, their effectiveness suggests that steroids have actions that can broadly be termed non-genomic. Such a beneficial cardiovascular effect of corticosteroids via a non-genomic mechanism has been reported by Hafezi-Moghadam et al. [1], who have shown that high levels of dexamethasone can induce activation of endothelial nitric oxide synthase (eNOS) and also reduce

infarct size in a murine model of transient myocardial ischaemia. Dexamethasoneinduced activation of eNOS was concentration-dependent and manifest within 10 min. Furthermore, this effect could be blocked by wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K), but not by the transcriptional inhibitor actinomycin D. This suggested that these effects of dexamethasone were not mediated via gene transcription but by a direct signalling pathway. Activation of eNOS was inhibited by the glucocorticoid receptor (GR) antagonist RU486, suggesting that it was mediated by the intracellular GR. However, activation of eNOS was not related to the activity of the glucocorticoid response element (GRE) promoter sequences and, whereas actinomycin D inhibited GRE promoter activity as expected, wortmannin did not. Hence, this study claims that binding of high concentrations

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