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Snapshot: Ca2+-Dependent Transcription in Neurons Janine Zieg, Paul L

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Snapshot: Ca2+-Dependent Transcription in Neurons Janine Zieg, Paul L SnapShot: Ca2+-Dependent Transcription in Neurons Janine Zieg, Paul L. Greer, and Michael E. Greenberg Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA See online version for legend and references. Also see the September 25, 2008, Neuron Reviews Issue 1080 Cell 134, September 19, 2008 ©2008 Elsevier Inc. DOI 10.1016/j.cell.2008.09.010 entitled “Calcium Signaling at the Synapse.” SnapShot: Ca2+-Dependent Transcription in Neurons Janine Zieg, Paul L. Greer, and Michael E. Greenberg Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA Synaptic activity stimulates the influx of calcium ions into the postsynaptic neuron and thereby sets in motion a cascade of signaling events that lead to changes in gene expression. These changes in gene expression affect many aspects of nervous system development including dendritic morphogenesis, neuronal survival, and synapse development as well as the adaptive responses that underlie learning and memory in the mature nervous system. Mutations in components of the signal- ing pathways that participate in the process of experience-dependent brain development have been found to give rise to a variety of disorders of cognitive function including autism spectrum disorders. The initial contact between the axon and the dendrite during synapse development is mediated by cell surface-associated proteins on the pre- and postsynaptic membranes. For example, the binding of presynaptic β-neurexin to its postsynaptic receptor, Neuroligin1, leads to the recruitment of PSD-95 at nascent excitatory synapses. Ephrin/Eph signaling leads to the recruitment of additional proteins and the potentiation of NMDA receptor signaling. Release of the excitatory neurotrans- mitter glutamate from the presynaptic membrane and its binding to NMDA receptors and AMPA receptors on the postsynaptic membrane lead to the opening of these glutamate-gated ion channels. This is followed by membrane depolarization, opening of the L-type voltage-gated calcium ion channel (L-VSCC), and a rapid rise in calcium ions in the postsynaptic neuron as well as other local changes including protein recruitment and activation. Calcium entry through L-VSCCs leads to the recruitment of AKAP79/150, which then recruits PKA to the channel. PKA phosphorylates the calcium channel, thereby increasing its ability to allow calcium ions to flow into the cell. Calcium ion influx through L-VSCCs is sensed by calmodulin (CaM). Activated calmodulin initiates a cascade of events including stimulation of the guanine nucleotide exchange factor RasGRF, followed by activation of the Ras-MAPK signaling cascade. Calcium-activated calmodulin also activates the CaM kinase signaling pathway. Once activated these pathways trigger the phosphorylation and activation of a wide range of transcription factors such as CREB and NeuroD2. The phosphorylation of these transcription factors occurs in the nucleus and can be triggered by a cascade of events that begins at the site of calcium entry at the mouth of the calcium channel (that is, the Ras, Raf, MEK, ERK, RSK/MSK signaling pathway). Alternatively, channel activation can trigger an elevation of calcium ions directly in the nucleus that leads to activation of nuclear CaMKII by calcium/calmodulin, which in turn phosphorylates CREB and NeuroD2. In addition, dephosphorylation- dependent signaling through calcium/calmodulin activation of calcineurin leads to the activation of the transcripton factors NFAT and MEF2. Once activated and localized to the nucleus, calcium-activated transcription factors and modulators of transcription bind to the regulatory regions of activity- regulated genes to orchestrate finely tuned levels of gene expression. The most extensively studied activity-regulated gene isBdnf , the gene encoding brain-derived neurotrophic factor. BDNF affects numerous processes in neuronal development including axonal and dendritic development, synapse formation and maturation, syn- aptic potentiation, and neuronal survival. Polymorphisms in the Bdnf gene correlate with defects in learning and memory. The promoter region of Bdnf is complex and includes at least seven different 5′ exons, only some of which are regulated by synaptic activity. At activity-regulated promoter IV, CREB, USF1/2, and CaRF occupy three distinct calcium response elements: CaRE1, CaRE2, and CaRE3. Neuronal activity leads to the activation of CREB by phosphorylation at three serine residues (Ser133, 142, and 143) through the combined action of kinases including RSK, CaMKII, and CaMKIV. Activated CREB binds to its cofactor, the histone acetyl trans- ferase CBP, to promote Bdnf transcription. CREB activation of Bdnf transcription may be modulated by CREM, which is itself an activity-regulated CREB-dependent gene. MEF2, activated through dephosphoryation by calcineurin, positively regulates Bdnf expression. Prior to neurotransmitter release onto the postsynaptic neuron, MEF2 binds to transcriptional corepressors mSin3a, SUV39H, and HDACs. NF-κB, activated by CaMKII-dependent phosphorylation in the cytoplasm, translocates to the nucleus to positively regulate Bdnf expression. Npas4, a PAS-domain bHLH transcription factor known to promote inhibitory synapse formation on excitatory neurons, also binds to Bdnf promoter IV and appears to sustain BDNF expression. Translation of MeCP2 mRNA is regulated by a CREB-dependent microRNA, and the MeCP2 protein, a methyl-CpG-binding protein, is phosphorylated by CaMKII at Ser421. MeCP2 modulation of Bdnf expression is complex and is important in light of the involvement of MeCP2 in the etiology of Rett Syndrome. The complex of proteins that regulates Bdnf expression changes upon the influx of calcium ions into the postsynaptic neuron, in part through the CaMK-dependent phosphorylation of HDACs that control chromatin organization in the vicinity of Bdnf promoter IV. The release of HDACs is accompanied by the recruitment of the CREB-binding protein CBP, a histone acetyltransferase that engages the polymerase II transcriptional machinery. In addition to Bdnf, the expression of hundreds of other genes is also regulated by synaptic activity. Although the function of some of these genes is not understood, it is known that the activity-dependent regulation of gene expression promotes many diverse processes such as neuronal survival, dendrite formation, synaptic devel- opment, and adaptive responses. Interestingly, many of the molecules involved in these activity-dependent signal transduction pathways leading to activity-regulated gene expression are now known to be mutated in diseases of cognition such as autism spectrum disorders, suggesting that this activity-dependent program is im- portant for human nervous system development. Abbreviations AKAP, A-kinase anchor proteins; AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; Arc, activity-regulated cytoskeleton-associated pro- tein; Bcl, cell survival protein, name derived from B cell lymphoma 2; BDNF, brain-derived neurotrophic factor; bHLHB2, basic helix-loop-helix B2 transcription factor; CaM, calmodulin; CaMK, Calcium/calmodulin-dependent protein kinase; CaMKK, calcium/calmodulin-dependent protein kinase kinase; CaRF, calcium-responsive transcription factor; CBP, CREB-binding protein; c-fos, an immediate early gene transcription factor; CREB, cyclic AMP response element-binding protein; CREM, cyclic AMP response element modulator; DREAM, downstream regulatory element-antagonist modulator; ERK, extracellular signal-regulated kinases; HDAC, his- tone deacetylase; IAP, inhibitor of apoptosis; Kalirin-7, a Rho guanine nucleotide exchange factor that interacts with huntingtin-associated protein; L-VSCC, L-type voltage-sensitive calcium channel; MeCP2, methyl-CpG-binding protein 2; MEF2, myocyte enhancer factor 2; MEK, mitogen-activated protein kinase kinase; MiR132, microRNA132; MnSOD, manganese superoxide dismutase; mSin3a, mouse Sin3a transcription regulator; NeuroD2, neurogenic differentiation 2; NFAT, nuclear factor of activated T cells; NF-kB, nuclear factor kappa B; NMDAR, N-methyl-D-aspartic acid receptor; Npas4, neuronal PAS-domain bHLH transcription factor; Nur77, nerve growth factor IB; Pdyn, prodynorphin; Rac, member of the Rho family of GTPases; Raf, ras-activated factor; Ras, ras proto-oncogene; RasGRF, ras protein- specific guanine nucleotide-releasing factor; RSK, ribosomal s6 kinase; Src, proto-oncogenic tyrosine kinase similar to v-Src protein from Rous Sarcoma Virus; Tiam, T cell lymphoma invasion and metastasis-inducing protein; USF, upstream stimulatory factor; Wnt2, wingless-type MMTV integration site family, member 2; ?, as- sociations have been shown in nonneuronal cell types. REFERENCES Chahrour, M., Jung, S.Y., Shaw, C., Zhou, X., Wong, S.T., Qin, J., and Zoghbi, H.Y. (2008). MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229. Flavell, S.W., Cowan, C.W., Kim, T.K., Greer, P.L., Lin, Y., Paradis, S., Griffith, E.C., Hu, L.S., Chen, C., and Greenberg, M.E. (2006). Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311, 1008–1012. Husi, H., Ward, M.A., Choudhary, J.S., Blackstock, W.P., and Grant, S.G. (2000). Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat. Neurosci. 3, 661–669. Impey, S., McCorkle, S.R., Cha-Molstad, H., Dwyer, J.M., Yochum, G.S., Boss, J.M., McWeeney, S., Dunn, J.J., Mandel, G., and Goodman, R.H. (2004). Defining the
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