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NMDAR in cultured astrocytes: Flux‐independent pH sensor and flux‐dependent regulator of mitochondria and plasma membrane‐mitochondria bridging
Author(s) -
Montes de Oca B Pavel,
Matus Núñez Mauricio ,
Picones Arturo,
HernandezCruz Arturo
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.00293
Subject(s) - nmda receptor , microbiology and biotechnology , mitochondrion , endoplasmic reticulum , biophysics , biology , depolarization , membrane potential , glutamate receptor , chemistry , biochemistry , receptor
Glutamate N‐methyl‐D‐aspartate (NMDA) receptor (NMDAR) is critical for neu‐rotransmission as a Ca2+ channel. Nonetheless, flux‐independent signaling has also been demonstrated. Astrocytes express NMDAR distinct from its neuronal counter‐part, but cultured astrocytes have no electrophysiological response to NMDA. We recently demonstrated that in cultured astrocytes, NMDA at pH6 (NMDA/pH6) act‐ing through the NMDAR elicits flux‐independent Ca2+ release from the Endoplasmic Reticulum (ER) and depletes mitochondrial membrane potential (mΔΨ). Here we show that Ca2+ release is due to pH6 sensing by NMDAR, whereas mΔΨ deple‐tion requires both: pH6 and flux‐dependent NMDAR signaling. Plasma membrane (PM) NMDAR guard a non‐random distribution relative to the ER and mitochon‐dria. 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 sug‐gest 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 Ca2+ release from most mitochondria. Finally, the MCU and microtubules were not involved in mΔΨ depletion, while actin cytoskeleton was partially involved. These findings demon‐strate that NMDAR has concomitant flux‐independent and flux‐dependent actions in cultured astrocytes. This work has been recently accepted for publication in The FASEB J.