Regulation of cpg15 by signaling pathways that mediate synaptic plasticity (original) (raw)

Promotion of dendritic growth by CPG15, an activity-induced signaling molecule

Science (New York, N.Y.), 1998

Activity-independent and activity-dependent mechanisms work in concert to regulate neuronal growth, ensuring the formation of accurate synaptic connections. CPG15, a protein regulated by synaptic activity, functions as a cell-surface growth-promoting molecule in vivo. In Xenopus laevis, CPG15 enhanced dendritic arbor growth in projection neurons, with no effect on interneurons. CPG15 controlled growth of neighboring neurons through an intercellular signaling mechanism that requires its glycosylphosphatidylinositol link. CPG15 may represent a new class of activity-regulated, membrane-bound, growth-promoting proteins that permit exquisite spatial and temporal control of neuronal structure.

Dynamic regulation of cpg15 during activity-dependent synaptic development in the mammalian visual system

The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999

During visual system development, neural activity regulates structural changes in connectivity including axonal branching and dendritic growth. Here we have examined a role for the candidate plasticity gene 15 (cpg15), which encodes an activity-regulated molecule that can promote dendritic growth, in this process. We report that cpg15 is expressed in the cat visual system at relatively high levels in the lateral geniculate nucleus (LGN) but at very low levels in its synaptic target, layer 4 of the visual cortex. Prenatally, when cpg15 mRNA in the LGN is most abundant, expression is insensitive to action potential blockade by tetrodotoxin. Postnatally, activity regulation of cpg15 emerges in the LGN coincident with development of ocular dominance columns in the visual cortex. cpg15 can be detected in layers 2/3 and 5/6 of visual cortex postnatally, and expression in layers 2/3 is activity-regulated during known periods of activity-dependent plasticity for these layers. Localization a...

Impaired synaptic plasticity and cAMP response element-binding protein activation in Ca2+/calmodulin-dependent protein kinase type IV/Gr-deficient mice

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000

The Ca(2+)/calmodulin-dependent protein kinase type IV/Gr (CaMKIV/Gr) is a key effector of neuronal Ca(2+) signaling; its function was analyzed by targeted gene disruption in mice. CaMKIV/Gr-deficient mice exhibited impaired neuronal cAMP-responsive element binding protein (CREB) phosphorylation and Ca(2+)/CREB-dependent gene expression. They were also deficient in two forms of synaptic plasticity: long-term potentiation (LTP) in hippocampal CA1 neurons and a late phase of long-term depression in cerebellar Purkinje neurons. However, despite impaired LTP and CREB activation, CaMKIV/Gr-deficient mice exhibited no obvious deficits in spatial learning and memory. These results support an important role for CaMKIV/Gr in Ca(2+)-regulated neuronal gene transcription and synaptic plasticity and suggest that the contribution of other signaling pathways may spare spatial memory of CaMKIV/Gr-deficient mice.

Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity

Biochemical Society Transactions, 2009

NMDARs (N-methyl-D-aspartate receptors) are critical for synaptic function throughout the CNS (central nervous system). NMDAR-mediated Ca 2+ influx is implicated in neuronal differentiation, neuronal migration, synaptogenesis, structural remodelling, long-lasting forms of synaptic plasticity and higher cognitive functions. NMDAR-mediated Ca 2+ signalling in dendritic spines is not static, but can be remodelled in a cell-and synapse-specific manner by NMDAR subunit composition, protein kinases and neuronal activity during development and in response to sensory experience. Recent evidence indicates that Ca 2+ permeability of neuronal NMDARs, NMDARmediated Ca 2+ signalling in spines and induction of NMDAR-dependent LTP (long-term potentiation) at hippocampal Schaffer collateral-CA1 synapses are under control of the cAMP/ PKA (protein kinase A) signalling cascade. Thus, by enhancing Ca 2+ influx through NMDARs in spines, PKA can regulate the induction of LTP. An emerging concept is that activity-dependent regulation of NMDAR-mediated Ca 2+ signalling by PKA and by extracellular signals that modulate cAMP or protein phosphatases at synaptic sites provides a dynamic and potentially powerful mechanism for bi-directional regulation of synaptic efficacy and remodelling.

Protein kinase Mζ is essential for the induction and maintenance of dopamine-induced long-term potentiation in apical CA1 dendrites

2010

Dopaminergic D1/D5-receptor-mediated processes are important for certain forms of memory as well as for a cellular model of memory, hippocampal long-term potentiation (LTP) in the CA1 region of the hippocampus. D1/D5-receptor function is required for the induction of the protein synthesis-dependent maintenance of CA1-LTP (L-LTP) through activation of the cAMP/PKA-pathway. In earlier studies we had reported a synergistic interaction of D1/D5-receptor function and N-methyl-D-aspartate (NMDA)-receptors for L-LTP. Furthermore, we have found the requirement of the atypical protein kinase C isoform, protein kinase Mz (PKMz) for conventional electrically induced L-LTP, in which PKMz has been identified as a LTP-specific plasticity-related protein (PRP) in apical CA1-dendrites. Here, we investigated whether the dopaminergic pathway activates PKMz. We found that application of dopamine (DA) evokes a protein synthesis-dependent LTP that requires synergistic NMDA-receptor activation and protein synthesis in apical CA1-dendrites. We identified PKMz as a DA-induced PRP, which exerted its action at activated synaptic inputs by processes of synaptic tagging.

Protein Kinase C Regulates Local Synthesis and Secretion of a Neuropeptide Required for Activity-Dependent Long-Term Synaptic Plasticity

Journal of Neuroscience, 2007

Long-term facilitation (LTF) of sensory neuron synapses in Aplysia is produced by either nonassociative or associative stimuli. Nonassociative LTF can be produced by five spaced applications of serotonin (5-HT) and requires a phosphoinosotide 3-kinase (PI3K)dependent and rapamycin-sensitive increase in the local synthesis of the sensory neuron neuropeptide sensorin and a protein kinase A (PKA)-dependent increase in the secretion of the newly synthesized sensorin. We report here that associative LTF produced by a single pairing of a brief tetanus with one application of 5-HT requires a rapid protein kinase C (PKC)-dependent and rapamycin-sensitive increase in local sensorin synthesis. This rapid increase in sensorin synthesis does not require PI3K activity or the presence of the sensory neuron cell body but does require the presence of the motor neuron. The secretion of newly synthesized sensorin by 2 h after stimulation requires both PKA and PKC activities to produce associative LTF because incubation with exogenous anti-sensorin antibody or the kinase inhibitors after tetanus plus 5-HT blocked LTF. The secreted sensorin leads to phosphorylation and translocation of p42/44 mitogenactivated protein kinase (MAPK) into the nuclei of the sensory neurons. Thus, different stimuli activating different signaling pathways converge by regulating the synthesis and release of a neuropeptide to produce long-term synaptic plasticity.

Cyclic nucleotide gated channels as regulators of CNS development and plasticity

Current Opinion in Neurobiology, 1997

Cyclic nucleotide gated (CNG) cation channels are critical for signal transduction in vertebrate visual and olfactory systems. Members of the CNG channel gene family have now been cloned from a number of species, from Caenorhabditis elegans to humans. An important advance has been the discovery that CNG channels are present in many neurons of the mammalian brain. CNG channels act as molecular links between G-protein-coupled cascades, Can+-signalling systems, and gaseous messenger pathways. Perhaps most striking are recent data implicating CNG channels in both developmental and synaptic plasticity. Addresses Abbreviations c.AMP cGMP CNG channel co GFP LLA LTD LTP mGluR NMDA NO NOS ORN PCR adenosine 3',5'-cyclic monophosphate guanosine 3',5'-cyclic monophosphate cyclic nucleotide gated channel carbon monoxide green fluorescent protein long-lasting adaptation long-term depression long-term potentiation metabotropic glutamate receptor /V-methyl-o-aspartate nitric oxide NO synthase olfactory receptor neuron polymerase chain reaction CNG channels in CNS development and plasticity Zufall, Shepherd and Bamstable 405 Figure 1 (a) Rat rod a Mouse rod a Bovine rod a Dog rod a Human rod a Chick rod a Human cone a Bovine cone a Chick cone a Mouse olfactory a Rat olfactory a Rabbit aorta a Bovine olfactory a Catfish olfactory a Rat olfactory b C. elegans tax-4 Bovine rod b Human rod 0 C. elegans tax-2 Drosophilia CNGCl W 0 1997 Current Opinm I" Neurobiology CNG channel gene family and structure. (a) The protein sequences of the 20 CNG channel subunits cloned so far were obtained from GenBank and compared using the Hein algorithm in Align 2.14 (Lasergene, DNAstar Inc, Madison, USA). The resulting phylogenetic tree shows that mammalian rod a subunits are more similar to mammalian cone a subunits than they are to mammalian olfactory a subunits. The only exception to this classification is the rat olfactory j3 subunit, which this analysis suggests is more similar to a subunits than to mammalian rod or C. elegans p subunits. (b) A model of the topology of a CNG channel subunit. Much of the variation among channel subtypes resides in the large amino-terminal cytoplasmic domain. The transmembrane-spanning regions and the pore share substantial homology with some classes of voltage-gated K+ channels. The large carboxy-terminal cytoplasmic domain contains a cyclic-nucleotide-binding domain that shares substantial homology with equivalent regions in cyclic-nucleotide-dependent protein kinases and cyclic-nucleotide phosphodiesterases. CaM, calmodulin. Diagram courtesy of PA Kingston.

Activity-Dependent Synaptogenesis: Regulation by a CaM-Kinase Kinase/CaM-Kinase I/βPIX Signaling Complex

Neuron, 2008

Neuronal activity augments maturation of mushroom-shaped spines to form excitatory synapses, thereby strengthening synaptic transmission. We have delineated a Ca 2+-signaling pathway downstream of the NMDA receptor that stimulates calmodulin-dependent kinase kinase (CaMKK) and CaMKI to promote formation of spines and synapses in hippocampal neurons. CaMKK and CaMKI form a multiprotein signaling complex with the guanine nucleotide exchange factor (GEF) bPIX and GIT1 that is localized in spines. CaMKI-mediated phosphorylation of Ser516 in bPIX enhances its GEF activity, resulting in activation of Rac1, an established enhancer of spinogenesis. Suppression of CaMKK or CaMKI by pharmacological inhibitors, dominantnegative (dn) constructs and siRNAs, as well as expression of the bPIX Ser516Ala mutant, decreases spine formation and mEPSC frequency. Constitutively-active Pak1, a downstream effector of Rac1, rescues spine inhibition by dnCaMKI or bPIX S516A. This activity-dependent signaling pathway can promote synapse formation during neuronal development and in structural plasticity. Neuron Activity-Dependent Regulation of Synaptogenesis

The Two Regulatory Subunits of Aplysia cAMP-Dependent Protein Kinase Mediate Distinct Functions in Producing Synaptic Plasticity

Journal of Neuroscience, 2004

Activation of the cAMP-dependent protein kinase (PKA) is critical for both short-and long-term facilitation in Aplysia sensory neurons. There are two types of the kinase, I and II, differing in their regulatory (R) subunits. We cloned Aplysia RII; RI was cloned previously. Type I PKA is mostly soluble in the cell body whereas type II is enriched at nerve endings where it is bound to two prominent A kinaseanchoring-proteins (AKAPs). Disruption of the binding of RII to AKAPs by Ht31, an inhibitory peptide derived from a human thyroid AKAP, prevents both the short-and the long-term facilitation produced by serotonin (5-HT). During long-term facilitation, RII is transcriptionally upregulated; in contrast, the amount of RI subunits decreases, and previous studies have indicated that the decrease is through ubiquitin-proteosome-mediated proteolysis. Experiments with antisense oligonucleotides injected into the sensory neuron cell body show that the increase in RII protein is essential for the production of long-term facilitation. Using synaptosomes, we found that 5-HT treatment causes RII protein to increase at nerve endings. In addition, using reverse transcription-PCR, we found that RII mRNA is transported from the cell body to nerve terminals. Our results suggest that type I operates in the nucleus to maintain cAMP response element-binding protein-dependent gene expression, and type II PKA acts at sensory neuron synapses phosphorylating proteins to enhance release of neurotransmitter. Thus, the two types of the kinase have distinct but complementary functions in the production of facilitation at synapses of an identified neuron.