Membrane Stretch Gates NMDA Receptors.

Area of Science:

• Neuroscience
• Cellular Biology
• Mechanobiology

Background:

• N-methyl-D-aspartate receptors (NMDARs) are crucial ionotropic glutamate receptors in the CNS, mediating neurotransmission, synaptogenesis, and cellular toxicity.
• NMDARs function as glutamate-gated Ca²⁺ channels requiring glycine and are modulated by various cellular cues, including mechanical stimuli.
• Previous findings indicated shear stress initiates NMDAR-mediated Ca²⁺ entry in astrocytes without agonists, suggesting mechanical activation.

Purpose of the Study:

• To investigate whether mechanical membrane stretch can directly gate NMDAR currents in the absence of glutamate.
• To characterize the properties of stretch-activated NMDAR currents and compare them to glutamate-gated currents.
• To determine the role of the NMDAR intracellular domain in mechanical gating.

Main Methods:

• Controlled expression of rat recombinant NMDARs.
• Noninvasive on-cell single-channel current recordings.
• Application of controlled membrane stretch as a mechanical stimulus.

Main Results:

• Mild membrane stretch can substitute for glutamate in gating NMDAR currents.
• Stretch-activated currents exhibit hallmark features of glutamate-gated currents: glycine requirement, large unitary conductance, high Ca²⁺ permeability, and voltage-dependent Mg²⁺ blockade.
• The intracellular domain of the NMDAR is essential for stretch-gated current flow.

Conclusions:

• NMDARs can be mechanically activated by membrane stretch, independent of synaptic glutamate release.
• NMDARs function as mechanotransducers in the CNS, potentially initiating processes like synaptic plasticity and cytotoxicity.
• This discovery has significant implications for understanding mechanotransduction and the role of mechanical forces in CNS physiology and pathology, including traumatic brain injuries.