Abstract
While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca2+ influx. Extracellular Mg2+ at 2 mM did not significantly affect the shear induced Ca2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI.
Highlights
N-Methyl-D-aspartic acid receptors (NMDARs) are mediators of synaptic activity in the brain
NMDARs are mechanically sensitive in the absence of agonists
We visualized this behavior by using fluid shear stress as a uniform, precise and gentle mechanical stimulus
Summary
NMDARs are mechanically sensitive in the absence of agonists. We visualized this behavior by using fluid shear stress as a uniform, precise and gentle mechanical stimulus. Heureaux et al.[36] used a precalibrated probe of bilayer tension, the bacterial mechanical channel MscL, and found that the fluid shear stress they used would not activate MscL. Their predicted peak stress was twenty fold greater than what we used. There seem to be two possibilities: 1) the initial influx of Ca2+ raises local Ca2+ concentration activating a second messenger cascade such as CICR, or 2) the induced body stress caused a break of some cytoskeletal links and that led to plastic deformation of the cytoskeleton that was eventually coupled to bilayer tension. In a mechanically active tissue like muscle the mechanical sensitivity may dominate the glutamate sensitivity
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