Regulation of NMDA Receptors by Kinases and Phosphatases

Pitcher, Graham; Kalia, Lorraine V.; Liu, Xue Jun; Salter, Michael W.; Dong, Yina

doi:10.1201/9781420044157.ch7

Cited by 4 publications

(6 citation statements)

References 151 publications

(163 reference statements)

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“…The molecular and structural changes reported above led us to question the possible correspondence of these changes with changes in neuronal activity, the latter re ecting the functional state of neurons in terms of excitability (48). IL-1β reduced the number of spontaneous bursts in WT neurons, consistent with previous work correlating a decrease in spontaneous synaptic activity with a decrease in spine number (49), and with the fact that IL-1β alters LTP (50,51) and promotes excitotoxicity (52)(53)(54). Notably, the absence of MT5-MMP in TgMT5 -/cells prevented the alterations in spontaneous activity and spine density induced by IL-1β, further suggesting that MT5-MMP de ciency is synaptoprotective in the context of AD.…”

Section: Impact Of Mt5-mmp De Ciency and Il-1β On Neuronal Activitysupporting

confidence: 89%

Suppression of MT5-MMP reveals early modulation of Alzheimer’s pathogenic events in primary neuronal cultures of 5xFAD mice

Pilat,

Paumier,

Louis

et al. 2024

Preprint

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Background We previously reported that membrane-type 5-matrix metalloproteinase (MT5-MMP) deficiency not only reduces pathological hallmarks of Alzheimer’s disease (AD) in 5xFAD (Tg) mice in vivo, but also impairs interleukin-1 beta (IL-1β)-mediated neuroinflammation and Ab production in primary Tg immature neural cell cultures after 11 days in vitro. We now investigated the effect of MT5-MMP on incipient pathogenic pathways that are activated in cortical primary cultures at 21-24 days in vitro (DIV), during which neurons are organized into a functional mature network. Methods Using wild-type (WT), MT5-MMP-/- (MT5-/-), 5xFAD (Tg) and 5xFADxMT5-MMP-/- (TgMT5-/-) mice, we generated primary neuronal cultures that were exposed to IL-1b and/or different proteolytic system inhibitors. We assessed neuroinflammation, APP metabolism, synaptic integrity and electrophysiological properties using biochemical, imaging and whole- cell patch-clamp approaches. Results The absence of MT5-MMP impaired the IL-1b-mediated induction of inflammatory genes in TgMT5-/- cells compared to Tg cells. Furthermore, the reduced density of dendritic spines in Tg neurons was also prevented in TgMT5-/- neurons. IL-1b caused a strong decrease in the dendritic spine density of WT neurons, which was prevented in MT5-/- neurons. However, the latter exhibited fewer spines than the WT under untreated conditions. The spontaneous rhythmic firing frequency of the network was increased in MT5-/- neurons, but not in TgMT5-/- neurons and IL-1b increased this parameter only in Tg neurons. In terms of induced somatic excitability, Tg and TgMT5-/- neurons exhibited lower excitability than WT and MT5-/-, while IL-1b impaired excitability only on non-AD backgrounds. The synaptic strength of miniature global synaptic currents was equivalent in all genotypes, but increased dramatically in WT and MT5-/- neurons after IL-1b. MT5-MMP deficiency decreased endogenous and overexpressed C83 and C89 levels but did not affect Ab levels. C99 appears to be cleared by several pathways, including g-secretase, the autophagolysosomal system and also a-secretase, via its conversion to C83. Conclusion In summary, this study confirms that MT5-MMP is a pivotal factor affecting not only neuroinflammation and APP metabolism but also synaptogenesis and synaptic activity at early stages of the pathology, and reinforces the relevance of targeting MT5-MMP to fight AD.

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Section: Impact Of Mt5-mmp De Ciency and Il-1β On Neuronal Activitysupporting

confidence: 89%

Suppression of MT5-MMP reveals early modulation of Alzheimer’s pathogenic events in primary neuronal cultures of 5xFAD mice

Pilat,

Paumier,

Louis

et al. 2024

Preprint

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“…The phosphorylation status at several serine/threonine and tyrosine residues, particularly at the distal C‐terminus of NMDAR subunits involved with protein–protein interactions, 185 , 186 regulates several important functions related to synaptic plasticity by influencing the lateral diffusion and endocytosis of receptors. 50 , 52 , 177 , 187 , 188 , 189 In particular, phosphorlyation is the primary posttranslational modification that impacts protein–protein interactions, especially through regulation of receptor affinity with excitatory synaptic scaffolding proteins. These include membrane‐associated guanylate kinases (MAGUKs) such as postsynaptic density and synapse‐associated proteins (eg PSD‐95, SAP‐102, SAP‐97) that stabilize NMDAR synaptic location.…”

Section: Nmda Receptorsmentioning

confidence: 99%

“…NMDAR location and function is strongly regulated within minutes to hours by neuronal activity 37,65,159,171,172 through constitutive endocytosis with recycling endosomes, 43,173 vesicular exocytosis to the plasma membrane 30,174–176 and lateral diffusion between synaptic and extrasynaptic sites, 31,42,144,147,149,177–182 and this trafficking is subunit specific 43,159,173,183,184 (Figure 1). The phosphorylation status at several serine/threonine and tyrosine residues, particularly at the distal C‐terminus of NMDAR subunits involved with protein–protein interactions, 185,186 regulates several important functions related to synaptic plasticity by influencing the lateral diffusion and endocytosis of receptors 50,52,177,187–189 . In particular, phosphorlyation is the primary posttranslational modification that impacts protein–protein interactions, especially through regulation of receptor affinity with excitatory synaptic scaffolding proteins.…”

Section: Nmda Receptorsmentioning

confidence: 99%

“… 49 In addition, posttranslational modifications of subunits, particularly those impacting phosphorylation status, have a dramatic effect on protein–protein interactions at synapses and shift the direction of migration of receptors along the plasma membrane. 50 , 51 , 52 , 53 …”

Section: Introductionmentioning

confidence: 99%

“…Lateral diffusion is largely regulated by receptor subunit‐specific affinities with synaptic scaffolding proteins, 46–48 and an increase in the ability of synapses to accommodate new receptor entry also is important because augmented surface expression alone may change the character of synapses but will not increase their size 49 . In addition, posttranslational modifications of subunits, particularly those impacting phosphorylation status, have a dramatic effect on protein–protein interactions at synapses and shift the direction of migration of receptors along the plasma membrane 50–53 …”

Section: Introductionmentioning

confidence: 99%

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In the fast lane: Receptor trafficking during status epilepticus

Naylor

2023

Epilepsia Open

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Status epilepticus (SE) remains a significant cause of morbidity and mortality and often is refractory to standard first‐line treatments. A rapid loss of synaptic inhibition and development of pharmacoresistance to benzodiazepines (BZDs) occurs early during SE, while NMDA and AMPA receptor antagonists remain effective treatments after BZDs have failed. Multimodal and subunit‐selective receptor trafficking within minutes to an hour of SE involves GABA‐A, NMDA, and AMPA receptors and contributes to shifts in the number and subunit composition of surface receptors with differential impacts on the physiology, pharmacology, and strength of GABAergic and glutamatergic currents at synaptic and extrasynaptic sites. During the first hour of SE, synaptic GABA‐A receptors containing γ2 subunits move to the cell interior while extrasynaptic GABA‐A receptors with δ subunits are preserved. Conversely, NMDA receptors containing N2B subunits are increased at synaptic and extrasynaptic sites, and homomeric GluA1 (“GluA2‐lacking”) calcium permeant AMPA receptor surface expression also is increased. Molecular mechanisms, largely driven by NMDA receptor or calcium permeant AMPA receptor activation early during circuit hyperactivity, regulate subunit‐specific interactions with proteins involved with synaptic scaffolding, adaptin‐AP2/clathrin‐dependent endocytosis, endoplasmic reticulum (ER) retention, and endosomal recycling. Reviewed here is how SE‐induced shifts in receptor subunit composition and surface representation increase the excitatory to inhibitory imbalance that sustains seizures and fuels excitotoxicity contributing to chronic sequela such as “spontaneous recurrent seizures” (SRS). A role for early multimodal therapy is suggested both for treatment of SE and for prevention of long‐term comorbidities.

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Dysregulated Src upregulation of NMDA receptor activity: a common link in chronic pain and schizophrenia

Salter

Pitcher

2011

The FEBS Journal

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Upregulation of N-methyl-D-aspartate (NMDA) receptor function by the nonreceptor protein tyrosine kinase Src has been implicated in physiological plasticity at glutamatergic synapses. Here, we highlight recent findings suggesting that aberrant Src upregulation of NMDA receptors may also be key in pathophysiological conditions. Within the nociceptive processing network in the dorsal horn of the spinal cord, pathologically increased Src upregulation of NMDA receptors is critical for pain hypersensitivity in models of chronic inflammatory and neuropathic pain. On the other hand, in the hippocampus and prefrontal cortex, the physiological upregulation of NMDA receptors by Src is blocked by neuregulin 1-ErbB4 signaling, a pathway that is genetically implicated in the positive symptoms of schizophrenia. Thus, either over-upregulation or under-upregulation of NMDA receptors by Src may lead to pathological conditions in the central nervous system. Therefore, normalizing Src upregulation of NMDA receptors may be a novel therapeutic approach for central nervous system disorders, without the deleterious consequences of directly blocking NMDA receptors.

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Regulation of NMDA Receptors by Kinases and Phosphatases

Cited by 4 publications

References 151 publications

Suppression of MT5-MMP reveals early modulation of Alzheimer’s pathogenic events in primary neuronal cultures of 5xFAD mice

Suppression of MT5-MMP reveals early modulation of Alzheimer’s pathogenic events in primary neuronal cultures of 5xFAD mice

In the fast lane: Receptor trafficking during status epilepticus

Dysregulated Src upregulation of NMDA receptor activity: a common link in chronic pain and schizophrenia

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