Physiological Roles of Non-Neuronal NMDA Receptors

Hogan-Cann, Adam D.; Anderson, Christopher M.

doi:10.1016/j.tips.2016.05.012

Cited by 120 publications

(93 citation statements)

References 195 publications

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“…NMDAR, with high permeability to Ca 2+ , plays a crucial role in synaptic transmission and synaptic plasticity in the nervous system [37, 38]. A growing body of evidence indicates that NMDAR is also expressed in a wide range of non-neuronal cells, including cancer cells [39, 40]. To determine whether propofol decreased the levels of cellular Ca 2+ through NMDAR inactivation, we used MK801, an antagonist of NMDAR.…”

Section: Discussionmentioning

confidence: 99%

Propofol Disrupts Aerobic Glycolysis in Colorectal Cancer Cells via Inactivation of the NMDAR-CAMKII-ERK Pathway

Chen

Sun

et al. 2018

Cell Physiol Biochem

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Background/Aims: To investigate the effect of propofol on glucose metabolism in colorectal cancer cells and in an in vivo xenograft model. Methods: Glucose metabolism was assessed by measuring the extracellular acidification rate in HT29 and SW480 colorectal cancer cells. Quantitative real-time PCR and western blot analyses were used to detect mRNA and protein levels, respectively. Intracellular calcium was assessed by using a Fluo-3 AM fluorescence kit. Micro-positron emission tomography/computed tomography (microPET/CT) imaging was used to analyze glucose metabolism in the tumors of the xenograft model. Results: Propofol exposure induced a dose-dependent decrease of aerobic glycolysis in HT29 and SW480 colorectal cancer cells. MicroPET/CT indicated that propofol also inhibited ¹⁸F-FDG uptake in the xenograft model. In addition, hypoxia-inducible factor 1α (HIF1α) was also reduced by propofol dose-dependently. Propofol repressed the NMDAR-CAMKII-ERK pathway to inactivate HIF1α and therefore reduced glycolysis. Conclusion: Propofol inhibited aerobic glycolysis in colorectal cancer cells through the inactivation of the NMDAR-CAMKII-ERK pathway, which may facilitate a better understanding of the use of propofol in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

Propofol Disrupts Aerobic Glycolysis in Colorectal Cancer Cells via Inactivation of the NMDAR-CAMKII-ERK Pathway

Chen

Sun

et al. 2018

Cell Physiol Biochem

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“…This mechanism may be related to the expression of genes that let some authors conclude that cultured astrocytes represent an undifferentiated or activated phenotype of astrocytes. Nonetheless, since NMDAR is also expressed by endothelial cells, leukocytes, osteoblasts, platelets, or melanocytes, among other cells but also in a diversity of tissues including stomach, testis, thymus, ovaries, skin, pancreas, lung, kidney, or heart [3], it is likely that NMDAR function may encompass other mechanisms of action and regulation, beyond those described for synaptic or extrasynaptic NMDAR. For instance, leukocytes or endothelial cells are in contact with 40 times higher Glu (40 μM) in the blood than cells of CNS bathed by the cerebrospinal fluid (1 μM) [148].…”

Section: Insights Regarding Astrocytic Nmdarmentioning

confidence: 99%

“…Despite its wide expression and distribution in cells and tissues of mammals [3], NMDAR has been studied mainly in the neuronal context as a cationic channel [1,2]. Nevertheless, now we know that NMDAR is expressed not only by other cells of the CNS such as astrocytes or oligodendroglia but also in non-CNS cells such as endothelium, platelets, and lymphocytes, among others [3,[7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, now we know that NMDAR is expressed not only by other cells of the CNS such as astrocytes or oligodendroglia but also in non-CNS cells such as endothelium, platelets, and lymphocytes, among others [3,[7][8][9]. Moreover, there are some reports that have demonstrated NMDAR Ca 2+ flux-independent functions and signaling [10][11][12][13][14][15], but only few of them have explored the molecular mechanisms that underpin this function.…”

Section: Introductionmentioning

confidence: 99%

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NMDA Receptors in Astroglia: Chronology, Controversies, and Contradictions from a Complex Molecule

Balderas¹,

GonzálezHernández²

2018

Astrocyte - Physiology and Pathology

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The neurocentric theory dismissed for decades the role of glia in information handling within the central nervous system (CNS). Nevertheless, almost 3 decades ago, this started to change and today astrocytes are considered relevant players for this function. Astrocytes "listen" to neuronal communication, regulate it, and respond at the cellular and synctitial level. Ionotropic glutamate NMDA receptor (NMDAR) is critical in CNS. It mediates synaptic neuronal communication and it is involved in different mechanisms. However, NMDAR is also expressed by astrocytes, but its functional role in these cells has not been deeply investigated and has been a matter of debate in the last decades. In this chapter, we briefly outline NMDAR intracellular transduction pathways initiated by Ca 2+ flux. Then, we review chronologically NMDAR expression and function in astrocytes that have been a source of controversies and apparent contradictions. Finally, some insights are presented regarding NMDAR in astrocytes in the context of the tripartite synapse concept and the recently described Ca 2+ fluxindependent metabotropic-like NMDAR function in astrocytes. Given the complex molecular nature of NMDAR, its critical role, and the relevance of astrocytes, the study of astrocytic NMDAR promises to provide further understanding of CNS physiology and pathology.

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“…Also, NMDA/pH6 Dual function of NMDAR in astrocytes and PM-m-br 4 depleted mitochondrial membrane potential (m) [9]. In this work, we further study the signaling, cellular biology and biochemistry of the NMDAR to gain insight into its complex biology, that given its expression and diversity in different cells and tissues [16], it seems to be greater than conceived.We show here that NMDAR has a dual signaling function as a flux-independent pH sensor or as a flux-dependent channel that together with acid pH depletes m. In addition, our experiments along previous reports, strongly suggest that m is achieved by plasma membrane (PM) -mitochondria communication through structures referred here as PM-mitochondrial bridges (PM-m-br).…”

mentioning

confidence: 96%

Dual NMDAR signaling in astrocytes: flux-independent pH sensor & flux-dependent mitochondrial regulator through membrane-mitochondria communication

Balderas

Hernández‐Cruz

2019

Preprint

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Glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR) is critical for neurotransmission as a Ca2+ channel. Nonetheless, several reports have also demonstrated fluxindependent signaling. Astrocytes express NMDAR distinct from its neuronal counterpart, but cultured astrocytes have no electrophysiological response and controversial findings have questioned NMDAR function. We recently demonstrated that in cultured astrocytes NMDA at pH6 (NMDA/pH&) elicits flux-independent Ca2+ release from the Endoplasmic Reticulum (ER) and depletes mitochondrial membrane potential (m). Here we show that flux-independent Ca2+ release is mainly due to pH6, whereas m depletion requires both pH6 and flux-dependent NMDAR signaling. Immunofluorescence exhibited that plasma membrane (PM) NMDAR is apposed to ER and mitochondria or surrounds these organelles. Moreover, NMDA/pH6 treatment generated ER stress, increased endocytosis, mitochondria-ER and -nuclear contacts and strikingly, PM invaginations near mitochondria along with electrodense structures referred here as PMmitochondrial bridges (PM-m-br). These data and earlier observations strongly suggest PMmitochondria communication. As a proof of concept of this notion, NMDA/pH6 provoked mitochondria labeling by the PM dye FM-4-64FX. Finally, we analyzed by WB NMDAR subunit GluN1 to explore putative causes of NMDAR dual function, we found fragments with M.W. consistent with previously identified cleavage sites. Accordingly, GluN1 intracellular and extracellular domains presented little colocalization. Our findings demonstrate that NMDAR plays a dual function: a flux-independent pH sensor and a flux-dependent regulator of m. More importantly, m depletion seems to be mediated by PM-mitochondria communication. Finally, we found different GluN1 fragments that could be involved in NMDAR dual signaling, although causality awaits demonstration. NMDAR described so far, as it plays a central role for NMDAR assembly at the Endoplasmic Reticulum (ER) and its intracellular (IC) trafficking (1-3). However, NMDAR signaling is more complex, because Ca2+ inflow can switch on or off IC pathways with pro-survival or pro-death effects, suggested to be the result of synaptic or extra-synaptic NMDAR function, respectively (4). Moreover, several reports have also demonstrated flux-independent actions of this receptor (also termed metabotropic-like or non-canonical functions), that mediate long term depression (LTD) and other cellular events, through molecular mechanisms that have been only slightly investigated (5).In astrocytes, NMDAR expression and function were matter of debate for several years. However, nowadays it is clear that astrocytes in situ express functional NMDAR, although it displays several singularities, given in part by its subunit composition (6, 7). Nevertheless, classical electrophysiological experiments found no ionic flux in cultured astrocytes, and controversial findings have questioned NMDAR function (6,8). Nonetheless, we and others have recently demonstrated that the NMDAR ca...

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Physiological Roles of Non-Neuronal NMDA Receptors

Cited by 120 publications

References 195 publications

Propofol Disrupts Aerobic Glycolysis in Colorectal Cancer Cells via Inactivation of the NMDAR-CAMKII-ERK Pathway

Propofol Disrupts Aerobic Glycolysis in Colorectal Cancer Cells via Inactivation of the NMDAR-CAMKII-ERK Pathway

NMDA Receptors in Astroglia: Chronology, Controversies, and Contradictions from a Complex Molecule

Dual NMDAR signaling in astrocytes: flux-independent pH sensor & flux-dependent mitochondrial regulator through membrane-mitochondria communication

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