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• W2040278324 abstract "While Trk receptors can be activated in a neurotrophin-independent manner through “transactivation” by GPCR ligands, its physiological significance in the brain remains unknown. Huang et al. have now identified a novel mechanism of TrkB transactivation. They show that zinc ions can transactivate TrkB independent of neurotrophins and that such a transactivation is important for mossy fiber long-term potentiation (LTP). While Trk receptors can be activated in a neurotrophin-independent manner through “transactivation” by GPCR ligands, its physiological significance in the brain remains unknown. Huang et al. have now identified a novel mechanism of TrkB transactivation. They show that zinc ions can transactivate TrkB independent of neurotrophins and that such a transactivation is important for mossy fiber long-term potentiation (LTP). A dogma in the neurotrophin field, and indeed in cell signaling in general, is that neurotrophins signal by binding their cognate Trk receptors at the cell surface. Ligand binding initiates Trk receptor dimerization and phosphorylation via its intrinsic tyrosine kinase. Phosphorylated intracellular cytoplasmic tails of Trk act as docking sites for adaptor molecules, which in turn activate any/all of the three major downstream signaling pathways (Ras/MAPK/Erk, PI3K/Akt, and PLC-γ) to regulate neuronal survival, neurite outgrowth and branching, and synaptic transmission and plasticity (Huang and Reichardt, 2003Huang E.J. Reichardt L.F. Annu. Rev. Biochem. 2003; 72: 609-642Crossref PubMed Scopus (1824) Google Scholar). Until recently, Trk receptors were believed to be activated solely by neurotrophins. For example, TrkB is activated by either brain-derived neurotrophic factor (BDNF) or neurotrophin 4 (NT4). A neurotrophin-independent mechanism for TrkB activation was implicated by the observation that neither a null mutation of NT4 nor a conditional deletion of BDNF prevented TrkB activation during epileptogenesis (He et al., 2006He X.P. Butler L. Liu X. McNamara J.O. Neuroscience. 2006; 141: 515-520Crossref PubMed Scopus (8) Google Scholar, He et al., 2004He X.P. Kotloski R. Nef S. Luikart B.W. Parada L.F. McNamara J.O. Neuron. 2004; 43: 31-42Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar). Intriguing studies by Lee et al. (Lee and Chao, 2001Lee F.S. Chao M.V. Proc. Natl. Acad. Sci. USA. 2001; 98: 3555-3560Crossref PubMed Scopus (396) Google Scholar, Lee et al., 2002Lee F.S. Rajagopal R. Kim A.H. Chang P.C. Chao M.V. J. Biol. Chem. 2002; 277: 9096-9102Crossref PubMed Scopus (176) Google Scholar) provided evidence that, at least in cell culture, Trk signaling can occur independently of direct ligand/neurotrophin binding through “transactivation” by G protein-coupled receptor (GPCR) ligands such as adenosine or the neuropeptide PACAP. As the term suggests, transactivation refers to ligand-independent, indirect activation of receptor signaling. Further studies demonstrated that Trk receptors are activated intracellularly through Src kinase-mediated tyrosine phosphorylation. However, it was unclear whether molecules other than GPCR ligands can transactivate Trks. Moreover, the physiological significance of Trk receptor transactivation in the brain in vivo was also difficult to ascertain. The study by Huang et al. published in this issue of Neuron represents a major leap forward: the divalent cation zinc released in the hippocampal CA3 area in response to neural activity not only transactivates TrkB in vivo, but this transactivation plays a significant role in long-term potentiation (LTP) at the mossy fiber (MF)-CA3 synapses (Huang et al., 2008Huang Y.Z. Pan E. Xiong Z.-Q. McNamara J.O. Neuron. 2008; 57 (this issue): 546-558Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar). Previous studies have suggested that zinc (and copper) can activate TrkB by converting proBDNF to mature BDNF (mBDNF) through extracellular metalloproteinases (Hwang et al., 2005Hwang J.J. Park M.H. Choi S.Y. Koh J.Y. J. Biol. Chem. 2005; 280: 11995-12001Crossref PubMed Scopus (160) Google Scholar, Hwang et al., 2007Hwang J.J. Park M.H. Koh J.Y. J. Neurosci. Res. 2007; 85: 2160-2166Crossref PubMed Scopus (29) Google Scholar). In the present study, Huang et al. performed a series of experiments to show that zinc can directly activate TrkB in the absence of BDNF. First, zinc, but not other divalent or monovalent cations (Mg2+, Ca2+, K+, Na+, etc.), selectively activates TrkB (not TrkA or TrkC) and its downstream signaling pathways (Erk1/2, CREB, and PLC-γ). Second, zinc transactivates TrkB not only in wild-type (+/+) neurons when extracellular BDNF has been removed by the scavenger TrkB-IgG, but also in neurons derived from BDNF null mutant (−/−) or in TrkB-expressing heterologous cells. Third, zinc-induced TrkB activation was abolished by the Trk kinase inhibitor k252a and the extracellular zinc chelator Ca2+-EDTA, but activated by the zinc ionophore, sodium pyrithione. Finally, zinc does not occlude or display synergism with BDNF-induced TrkB activation, suggesting zinc-induced TrkB transactivation operates by a mechanism distinct from BDNF-induced activation. Using pharmacological approaches, Huang et al. also showed that zinc enters postsynaptic neurons through voltage-gated calcium channels (VGCCs) and NMDA receptors, but not through AMPA receptors. Following its entry, zinc activates Src family kinase (SFK) (Src, Yes, and Fyn) by relieving their autoinhibition. Src kinase, in turn, transactivates TrkB by phosphorylation, leading to its activation. An important contribution of the present study is to identify zinc as a new form of Trk transactivation, which is very different from that of GPCR ligands (Figure 1). First, while TrkB transactivation by extracellular ligands like adenosine and PACAP require cell surface GPCRs and Ca2+ influx, zinc enters postsynaptic neurons and transactivates TrkB intracellularly by inhibiting C-terminal Src kinase (CSK). Both mechanisms require Src to activate TrkB. Second, unlike GPCR ligands, which activate only PLC-γ and PI3 kinase/Akt pathways, zinc activates all the three major signaling pathways. Third, zinc transactivates TrkB more potently and much faster (minutes) than GPCR ligands (hours). Fourth, while zinc transactivates only full-length TrkB receptors localized to the postsynaptic density of excitatory synapses, GPCR ligands activate both surface localized mature Trk receptors and intracellularly localized immature Trk receptors (Figure 1). Finally, endogenous zinc stored in secretory vesicles is released at CA3 synapses in response to neuronal activity. Whether endogenous GPCR ligands are also released right at excitatory synapses in an activity-dependent manner is unclear. TrkB transactivation by endogenous cannabinoids (through cannabinoid receptor 1, CB1R) regulates the migration and morphogenesis of cholecystokinein-positive cortical interneurons during development (Berghuis et al., 2005Berghuis P. Dobszay M.B. Wang X. Spano S. Ledda F. Sousa K.M. Schulte G. Ernfors P. Mackie K. Paratcha G. et al.Proc. Natl. Acad. Sci. USA. 2005; 102: 19115-19120Crossref PubMed Scopus (203) Google Scholar). What is the physiological significance of TrkB transactivation by zinc (independent of BDNF) in the hippocampus? Zinc is enriched in synaptic vesicles through specialized zinc transporters at the MF-terminals and released along with glutamate in a Ca2+-dependent manner. Several studies have proposed a modulatory role for zinc in excitatory neurotransmission. Zinc influx into CA3 neurons through glutamate receptors has been shown to elicit a long-lasting synaptic potentiation in hippocampal slices (Li et al., 2001Li Y. Hough C.J. Frederickson C.J. Sarvey J.M. J. Neurosci. 2001; 21: 8015-8025Crossref PubMed Google Scholar). Huang et al. show that zinc-induced potentiation was abolished in hippocampal slices from TrkB−/− or drug-inducible TrkB mutants (TrkBF616A), suggesting a requirement for TrkB tyrosine kinase. Interestingly, zinc-induced synaptic potentiation still occurred in BDNF−/− slices. Thus, zinc-mediated potentiation at MF-CA3 synapses is due to TrkB transactivation rather than conventional BDNF-TrkB signaling. To examine the physiological relevance of zinc-induced TrkB transactivation, the authors studied LTP induced by high-frequency stimulation (HFS). While it is believed that MF-CA3 LTP is NMDA receptor-independent and is expressed presynaptically (Nicoll and Schmitz, 2005Nicoll R.A. Schmitz D. Nat. Rev. Neurosci. 2005; 6: 863-876Crossref PubMed Scopus (445) Google Scholar), results from this study favor a postsynaptic mechanism for zinc/TrkB-mediated LTP. Like zinc-induced potentiation, HFS elicited robust LTP at MF-CA3 synapses in wild-type hippocampal slices, but not in slices from TrkB−/− or drug-inducible TrkBF616A mutants. Moreover, removing extracellular zinc with the zinc chelator Ca2+-EDTA completely abolished HFS-induced LTP. The magnitude of LTP was only slightly reduced in BDNF−/− slices. The control Schaeffer collateral-CA1 LTP remained unaltered in the TrkB mutant when the same HFS was applied. Taken together, these results support a model in which high-frequency neuronal activity drives secretion of zinc, which in turn transactivates TrkB independently of BDNF to facilitate CA3 LTP (Figure 1). This novel mechanism may be operative in conjunction with the conventional, BDNF-dependent mechanism to regulate the function of mossy fiber synapses. The finding by Huang et al. provides new insights into the molecular mechanisms of MF-CA3 LTP, a process implicated in the storage and recall of information and pattern completion. A major function of zinc released at CA3 is to transactivate TrkB, which may facilitate mossy fiber LTP. Moreover, transactivation of TrkB by zinc may also have implications for our understanding of epilepsy etiology. The morphological and physiological changes that occur during limbic epileptogenesis (induced by kindling) in vivo closely resemble that of HFS-induced LTP at MF-CA3 synapses (Goussakov et al., 2000Goussakov I.V. Fink K. Elger C.E. Beck H. J. Neurosci. 2000; 20: 3434-3441PubMed Google Scholar). In fact, deletion of TrkB prevented epileptogenesis in the kindling model (He et al., 2004He X.P. Kotloski R. Nef S. Luikart B.W. Parada L.F. McNamara J.O. Neuron. 2004; 43: 31-42Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar). Therefore, zinc-mediated TrkB transactivation may contribute to the underlying cellular mechanisms recruited during epileptogenesis. The study by Huang et al. strongly supports a BDNF-independent mechanism of zinc-induced TrkB activation. However, several biochemical experiments performed under similar conditions have yielded contradictory results that are hard to reconcile (Hwang et al., 2005Hwang J.J. Park M.H. Choi S.Y. Koh J.Y. J. Biol. Chem. 2005; 280: 11995-12001Crossref PubMed Scopus (160) Google Scholar). For instance, in the current study the zinc ionophore sodium pyrithione was able to enhance zinc-induced TrkB transactivation, while under almost identical conditions it had no effect in the previous study. Chelating zinc by Ca2+-EDTA here completely eliminated the zinc effect, whereas the previous experiment using BAPTA-AM failed to block zinc-induced TrkB phosphorylation. An anti-BDNF antibody inhibited TrkB activation in the earlier study. In contrast, Huang et al. now show that TrkB transactivation still occurs in neurons treated with TrkB-IgG or in those derived from BDNF−/− mice. Further experiments using BDNF/NT4 double-knockout mice should exclude the possibility of NT4-dependent TrkB activation in the absence of BDNF. These results argue for two completely different mechanisms for zinc-mediated TrkB activation. It is difficult to imagine how the BDNF neutralizing antibodies and matrix metalloproteinase inhibitors used in the previous study could abolish zinc-induced TrkB transactivation by a BDNF-independent mechanism, which is proposed in this study. Further studies are necessary to resolve these discrepancies. While the results from this study unveil a novel mechanism of TrkB transactivation and its downstream signaling, they also raise several important questions, which should be addressed by future research (Figure 1). For example, how does neuronal activity govern zinc entry to regulate CSK activity? Does zinc inhibit CSK directly or indirectly? How does Src specifically regulate TrkB (not Trk C or A) activation? Since both zinc and BDNF activate TrkB in similar manners, are there differences in their biological outcomes? If not, why has nature evolved two similar, if not identical, mechanisms to govern TrkB activation? Based on the new findings, it is tempting to propose zinc as a therapeutic agent for neurodegenerative disorders, since it does not have the usual problems of stability and CNS delivery that are associated with neurotrophin proteins. Zinc-Mediated Transactivation of TrkB Potentiates the Hippocampal Mossy Fiber-CA3 Pyramid SynapseHuang et al.NeuronFebruary 28, 2008In BriefThe receptor tyrosine kinase, TrkB, is critical to diverse functions of the mammalian nervous system in health and disease. Evidence of TrkB activation during epileptogenesis in vivo despite genetic deletion of its prototypic neurotrophin ligands led us to hypothesize that a non-neurotrophin, the divalent cation zinc, can transactivate TrkB. We found that zinc activates TrkB through increasing Src family kinase activity by an activity-regulated mechanism independent of neurotrophins. One subcellular locale at which zinc activates TrkB is the postsynaptic density of excitatory synapses. 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• W2040278324 title "Ama“Zinc” Link between TrkB Transactivation and Synaptic Plasticity" @default.
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