Membrane Stretch Gates NMDA Receptors

Abstract

N-Methyl-D-aspartic (NMDA) receptors are excitatory glutamate-gated ion channels. Their activation is essential for the normal development, maintenance, and plasticity of excitatory synapses in the central nervous system. They function as glutamate-gated Ca2+-permeable channels, require glycine as co-agonist, and can be modulated by myriad of diffusible ligands and cellular cues, including mechanical stimuli. Previously, we found that in cultured astrocytes, shear stress initiates NMDA receptor-mediated Ca2+ entry in the absence of added agonists, suggesting that in addition to being mechanosensitive, NMDA receptors may be mechanically activated. Here, we used controlled expression of recombinant receptors and non-invasive on-cell single-channel current recordings to show that gentle membrane stretch can substitute for the neurotransmitter glutamate in gating NMDA receptor currents. Notably, stretch-activated currents preserved the hallmark features of the glutamate-gated currents, including glycine-requirement, large unitary conductance, high Ca2+ permeability, and voltage-dependent Mg2+ blockade. Further, we found that the stretch-gated current required the receptors intracellular domain, which may suggest a force-from-filament sensing mechanism. These results are consistent with the hypothesis that mechanical forces can gate NMDA receptor currents even in the absence of synaptic glutamate release, which has important implications for understanding mechanotransduction and the effect of mechanical forces on cells of the central nervous system. HighlightsO_LIMembrane stretch gates NMDA receptor currents in the absence of the neurotransmitter glutamate. C_LIO_LIStretch-gated currents maintain the characteristic features of glutamate-gated currents, including glycine requirement, Ca2+ permeability, and voltage-dependent Mg2+ block. C_LIO_LIGating of NMDA receptor by membrane stretch requires the receptors intracellular domain. C_LIO_LIMild stretch of neuronal membranes gate native NMDA receptor currents. C_LI SummaryMembrane stretch gates NMDA receptor currents in the absence of neurotransmitter. Stretch-gated currents have the biophysical hallmarks of the glutamate-gated currents including requirement for glycine, large Na+ conductance, high Ca2+ permeability, and voltage-dependent Mg2+ block.