Group I Metabotropic Glutamate Receptor Signaling via Gαq/Gα11 Secures the Induction of Long-Term Potentiation in the Hippocampal Area CA1

Miura, Masami; Watanabe, Masahiko; Offermanns, Stefan; Simon, Melvin I.; Kano, Masanobu

doi:10.1523/jneurosci.22-19-08379.2002

Cited by 50 publications

(29 citation statements)

References 72 publications

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“…In contrast, mGluR activation drives trafficking of GluR mRNAs into dendrites (present study) and promotes local on-site protein synthesis (Kacharmina et al, 2000;Ju et al, 2004). Whereas mGluR activation promotes AMPAR endocytosis and LTD on the order of minutes, mGluR LTD is followed by priming of LTP, a state in which persistent enhanced membrane excitability facilitates LTP induction on the order of hours (Cohen and Abraham, 1996;Cohen et al, 1999;Raymond et al, 2000;Miura et al, 2002). We propose that enhanced levels of GluR mRNAs in dendrites may represent a mechanism relevant to priming.…”

Section: Physiological Significance Of Regulated Trafficking Of Amparmentioning

confidence: 61%

Activity Bidirectionally Regulates AMPA Receptor mRNA Abundance in Dendrites of Hippocampal Neurons

Grooms¹,

Noh²,

Regis³

et al. 2006

J. Neurosci.

150

127

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Activity-dependent regulation of synaptic AMPA receptor (AMPAR) number is critical to NMDA receptor (NMDAR)-dependent synaptic plasticity. Using quantitative high-resolution in situ hybridization, we show that mRNAs encoding the AMPA-type glutamate receptor subunits (GluRs) 1 and 2 are localized to dendrites of hippocampal neurons and are regulated by paradigms that alter synaptic efficacy. A substantial fraction of synaptic sites contain AMPAR mRNA, consistent with strategic positioning and availability for "on-site" protein synthesis. NMDAR activation depletes dendritic levels of AMPAR mRNAs. The decrease in mRNA occurs via rise in intracellular Ca 2ϩ , activation of extracellular signal-regulated kinase/mitogen-activated protein kinase signaling, and transcriptional arrest at the level of the nucleus. The decrease in mRNA is accompanied by a long-lasting reduction in synaptic AMPAR number, consistent with reduced synaptic efficacy. In contrast, group I metabotropic GluR signaling promotes microtubule-based trafficking of existing AMPAR mRNAs from the soma to dendrites. Bidirectional regulation of dendritic mRNA abundance represents a potentially powerful means to effect long-lasting changes in synaptic strength.

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Section: Physiological Significance Of Regulated Trafficking Of Amparmentioning

confidence: 61%

Activity Bidirectionally Regulates AMPA Receptor mRNA Abundance in Dendrites of Hippocampal Neurons

Grooms¹,

Noh²,

Regis³

et al. 2006

J. Neurosci.

150

127

View full text Add to dashboard Cite

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“…A direct relationship between G␣ q/11 dysfunction and the pathogenesis of AD leading to neurodegeneration and dementia is suggested by the important role of G␣ q/11 proteins in neuronal survival and memory (9,10,39,40). In addition, many of the cognitionenhancing effects of acetylcholine in mice are mediated by G␣ q/11 -coupled muscarinic receptors (39).…”

Section: Discussionmentioning

confidence: 99%

“…G␣ q/11 -stimulated signal transduction pathways are important for neuronal communication, synaptic plasticity, and neuronal survival (9,10). Therefore, it is likely that the G␣ q/11 signaling defect of AD patients plays a role in the disease process leading to neurodegeneration and dementia.…”

mentioning

confidence: 99%

Angiotensin II AT2 Receptor Oligomers Mediate G-protein Dysfunction in an Animal Model of Alzheimer Disease

AbdAlla

Lother

Missiry

et al. 2009

Journal of Biological Chemistry

105

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Progressive neurodegeneration and decline of cognitive functions are major hallmarks of Alzheimer disease (AD). Neurodegeneration in AD correlates with dysfunction of diverse signal transduction mechanisms, such as the G-protein-stimulated phosphoinositide hydrolysis mediated by G␣ q/11 . We report here that impaired G␣ q/11 -stimulated signaling in brains of AD patients and mice correlated with the appearance of crosslinked oligomeric angiotensin II AT 2 receptors sequestering G␣ q/11 . Amyloid ␤ (A␤) was causal to AT 2 oligomerization, because cerebral microinjection of A␤ triggered AT 2 oligomerization in the hippocampus of mice in a dose-dependent manner. A␤ induced AT 2 oligomerization by a two-step process of oxidative and transglutaminase-dependent cross-linking. The induction of AT 2 oligomers in a transgenic mouse model with AD-like symptoms was associated with G␣ q/11 dysfunction and enhanced neurodegeneration. Vice versa, stereotactic inhibition of AT 2 oligomers by RNA interference prevented the impairment of G␣ q/11 and delayed Tau phosphorylation. Thus, A␤ induces the formation of cross-linked AT 2 oligomers that contribute to the dysfunction of G␣ q/11 in an animal model of Alzheimer disease. Alzheimer disease (AD)2 is a protein aggregation disease that is characterized by profound neuropathological changes in the brain, including neurodegeneration, neurofibrillary tangles, and the accumulation of fibrillar ␤-amyloid (A␤) in extracellular senile plaques. Although some neuropathological features of AD, such as tangles and plaques, are also detected in brains of elderly people without major symptoms of dementia (1), neurodegeneration and neuronal loss of AD patients are associated with the major AD symptoms of memory impairment and dementia (2, 3). Neurodegeneration in AD is accompanied by dysfunction of diverse signal transduction mechanisms, such as the G-protein-stimulated phosphoinositide hydrolysis mediated by G␣ q/11 (4 -8). G␣ q/11 -stimulated signal transduction pathways are important for neuronal communication, synaptic plasticity, and neuronal survival (9, 10). Therefore, it is likely that the G␣ q/11 signaling defect of AD patients plays a role in the disease process leading to neurodegeneration and dementia. In agreement with this notion, G-protein dysfunction is directly associated with disease severity of AD patients (8).Further insight into the pathological role of the G-protein dysfunction of AD patients is lacking, because the underlying mechanism is barely understood. Several observations point to a specific defect at the level of G␣ q/11 : (i) protein levels of G␣ q/11 are not changed (7); (ii) downstream receptor/G-protein-independent phosphoinositide hydrolysis is intact (7); and (iii) receptor-mediated activation of other G-proteins, such as the G␣ i/o proteins, is not affected (5). In view of a putative role in the pathogenesis, we investigated the mechanism accounting for defective G␣ q/11 activation in AD.G␣ q/11 activation is under control of specific receptors. Although mo...

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“…It is tempting to draw a parallel between these molecular results and LTP induction. Under low stimulation conditions, coactivation of both NMDARs and mGluRs have been reported to be needed for LTP induction (Miura et al, 2002;Kotecha et al, 2003) and that PKC inhibitors but not IP 3 antagonists were shown to block LTP (Fujii et al, 2004).…”

Section: Synergistic Activation Of Pkc␥ After Iglur and Mglur Stimulamentioning

confidence: 99%

Synergistic Control of Protein Kinase Cγ Activity by Ionotropic and Metabotropic Glutamate Receptor Inputs in Hippocampal Neurons

Codazzi¹,

Cesare²,

Chiulli³

et al. 2006

J. Neurosci.

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Conventional protein kinase C (PKC) isoforms are abundant neuronal signaling proteins with important roles in regulating synaptic plasticity and other neuronal processes. Here, we investigate the role of ionotropic and metabotropic glutamate receptor (iGluR and mGluR, respectively) activation on the generation of Ca 2ϩ and diacylglycerol (DAG) signals and the subsequent activation of the neuronspecific PKC␥ isoform in hippocampal neurons. By combining Ca 2ϩ imaging with total internal reflection microscopy analysis of specific biosensors, we show that elevation of both Ca 2ϩ and DAG is necessary for sustained translocation and activation of EGFP (enhanced green fluorescent protein)-PKC␥. Both DAG production and PKC␥ translocation were localized processes, typically observed within discrete microdomains along the dendritic branches. Markedly, intermediate-strength NMDA receptor (NMDAR) activation or moderate electrical stimulation generated Ca 2ϩ but no DAG signals, whereas mGluR activation generated DAG but no Ca 2ϩ signals. Both receptors were needed for PKC␥ activation. This suggests that a coincidence detection process exists between iGluRs and mGluRs that relies on a molecular coincidence detection process based on the corequirement of Ca 2ϩ and DAG for PKC␥ activation. Nevertheless, the requirement for costimulation with mGluRs could be overcome for maximal NMDAR stimulation through a direct production of DAG via activation of the Ca 2ϩ -sensitive PLC␦ (phospholipase C␦) isoform. In a second important exception, mGluRs were sufficient for PKC␥ activation in neurons in which Ca 2ϩ stores were loaded by previous electrical activity. Together, the dual activation requirement for PKC␥ provides a plausible molecular interpretation for different synergistic contributions of mGluRs to long-term potentiation and other synaptic plasticity processes.

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Group I Metabotropic Glutamate Receptor Signaling via Gαq/Gα11 Secures the Induction of Long-Term Potentiation in the Hippocampal Area CA1

Cited by 50 publications

References 72 publications

Activity Bidirectionally Regulates AMPA Receptor mRNA Abundance in Dendrites of Hippocampal Neurons

Activity Bidirectionally Regulates AMPA Receptor mRNA Abundance in Dendrites of Hippocampal Neurons

Angiotensin II AT2 Receptor Oligomers Mediate G-protein Dysfunction in an Animal Model of Alzheimer Disease

Synergistic Control of Protein Kinase Cγ Activity by Ionotropic and Metabotropic Glutamate Receptor Inputs in Hippocampal Neurons

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