Metalloproteases in Adaptative Cell Responses

Balderas, Pavel Montes de Oca

doi:10.1007/978-981-10-2513-6_7

Cited by 3 publications

(3 citation statements)

References 127 publications

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“…Taken together, these evolutionary traits of the NMDAR and ionotropic Glu receptors, along with the flux-independent function present in other channel families, strongly suggest that f-iNMDARs is ancestral, present in other non-mammal taxa with related ionotropic-like Glu receptors, and conserved through evolution, further supporting that f-iNMDARs may have a more relevant role than acknowledged. Interestingly, the dual signaling function of the NMDAR is also consistent with the natural selection of multi-functional molecules, known to occur with respect to cell membrane molecules [73,74]. Ultimately, it would be interesting to analyze the evolutionary conditions that favoured the emergence of the NMDAR, that requires agonist and co-agonist binding for its opening, a feature unique among Glu receptors, and to assess its advantage for the fitness of cnidarians and the groups that conserved it.…”

Section: Insightsmentioning

confidence: 55%

Flux-Independent NMDAR Signaling: Molecular Mediators, Cellular Functions, and Complexities

Balderas

2018

IJMS

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The glutamate (Glu) N-methyl-d-aspartate (NMDA) receptor (NMDAR) plays a critical role in synaptic communication given mainly by its ionotropic function that permeates Ca2+. This in turn activates calmodulin that triggers CaMKII, MAPK, CREB, and PI3K pathways, among others. However, NMDAR signaling is more complex. In the last two decades several groups have shown that the NMDAR also elicits flux-independent signaling (f-iNMDARs). It has been demonstrated that agonist (Glu or NMDA) or co-agonist (Glycine or d-Serine) bindings initiate intracellular events, including conformational changes, exchange of molecular interactions, release of second messengers, and signal transduction, that result in different cellular events including endocytosis, LTD, cell death, and neuroprotection, among others. Interestingly, f-iNMDARs has also been observed in pathological conditions and non-neuronal cells. Here, the molecular and cellular events elicited by these flux-independent actions (non-canonical or metabotropic-like) of the NMDAR are reviewed. Considering the NMDAR complexity, it is possible that these flux-independent events have a more relevant role in intracellular signaling that has been disregarded for decades. Moreover, considering the wide expression and function of the NMDAR in non-neuronal cells and other tissues beyond the nervous system and some evolutionary traits, f-iNMDARs calls for a reconsideration of how we understand the biology of this complex receptor.

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Section: Insightsmentioning

confidence: 55%

Flux-Independent NMDAR Signaling: Molecular Mediators, Cellular Functions, and Complexities

Balderas

2018

IJMS

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“…Considering the electrodensity of PM‐m‐br, it is possible to conceive that such structures may mediate the transfer of PM molecules, 22 which most probably include cleaved PM proteins, 63,64 but also of other organic molecules or ions. As a proof of concept of mass transfer from PM to mitochondria, the lipophilic PM dye FM 4‐64FX reached mitochondria shortly (100 seconds) after NMDA/pH6.…”

Section: Discussionmentioning

confidence: 99%

NMDAR in cultured astrocytes: Flux‐independent pH sensor and flux‐dependent regulator of mitochondria and plasma membrane‐mitochondria bridging

et al. 2020

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Glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR) is critical for neurotransmission as a Ca 2+ channel. Nonetheless, flux-independent signaling has also been demonstrated. Astrocytes express NMDAR distinct from its neuronal counterpart, but cultured astrocytes have no electrophysiological response to NMDA. We recently demonstrated that in cultured astrocytes, NMDA at pH6 (NMDA/pH6) acting through the NMDAR elicits flux-independent Ca 2+ release from the Endoplasmic Reticulum (ER) and depletes mitochondrial membrane potential (mΔΨ). Here we show that Ca 2+ release is due to pH6 sensing by NMDAR, whereas mΔΨ depletion requires both: pH6 and flux-dependent NMDAR signaling. Plasma membrane (PM) NMDAR guard a non-random distribution relative to the ER and mitochondria. Also, NMDA/pH6 induces ER stress, endocytosis, PM electrical capacitance reduction, mitochondria-ER, and-nuclear contacts. Strikingly, it also produces the formation of PM invaginations near mitochondria along with structures referred to here as PM-mitochondrial bridges (PM-m-br). These and earlier data strongly suggest PM-mitochondria communication. As proof of the concept of mass transfer, we found that NMDA/pH6 provoked mitochondria labeling by the PM dye FM-4-64FX. NMDA/pH6 caused PM depolarization, cell acidification, and Ca 2+ release from most mitochondria. Finally, the MCU and microtubules were not involved in mΔΨ depletion, while actin cytoskeleton was partially involved. These findings demonstrate that NMDAR has concomitant flux-independent and flux-dependent actions in cultured astrocytes. K E Y W O R D S astrocyte, calcium, flux-independent, mitochondria, NMDAR, organelle communication | 16623 MONTES dE OCA BALdERAS ET AL.

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“…This in turn could pre-activate or sensitize Spike fusion micromachine, modify its conformation during viral cell exit pathway and/or modify viral tropism [5]. Moreover, it has been shown that Spike S1 domain is shed after furin cleavage [6], a proteolytic molecular mechanism that is common for plasma membrane molecules [7]. These structure-function considerations raise the possibility that furin cleavage acts as a bypass for the activation of the membrane fusion mechanism and/or that it may help the virus to evade the immune response as it has been suggested [6].…”

Section: Introductionmentioning

confidence: 99%

Is the Innate Immune Response Involved in the Transient Protection Provided by Spike-Based COVID-19 Vaccines?

Balderas

2023

AJBSR

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Metalloproteases in Adaptative Cell Responses

Cited by 3 publications

References 127 publications

Flux-Independent NMDAR Signaling: Molecular Mediators, Cellular Functions, and Complexities

Flux-Independent NMDAR Signaling: Molecular Mediators, Cellular Functions, and Complexities

NMDAR in cultured astrocytes: Flux‐independent pH sensor and flux‐dependent regulator of mitochondria and plasma membrane‐mitochondria bridging

Is the Innate Immune Response Involved in the Transient Protection Provided by Spike-Based COVID-19 Vaccines?

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