Back to Search Start Over

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

Authors :
Montes de Oca Balderas P
Matus Núñez M
Picones A
Hernández-Cruz A
Source :
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2020 Dec; Vol. 34 (12), pp. 16622-16644. Date of Electronic Publication: 2020 Nov 01.
Publication Year :
2020

Abstract

Glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR) is critical for neurotransmission as a Ca <superscript>2+</superscript> 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 <superscript>2+</superscript> release from the Endoplasmic Reticulum (ER) and depletes mitochondrial membrane potential (mΔΨ). Here we show that Ca <superscript>2+</superscript> 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 <superscript>2+</superscript> 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.<br /> (© 2020 Federation of American Societies for Experimental Biology.)

Details

Language :
English
ISSN :
1530-6860
Volume :
34
Issue :
12
Database :
MEDLINE
Journal :
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Publication Type :
Academic Journal
Accession number :
33131132
Full Text :
https://doi.org/10.1096/fj.202001300R