Remembering Mechanosensitivity of NMDA Receptors

Abstract

An increase in post-synaptic Ca²⁺ conductance through activation of the ionotropic N-methyl-D-aspartate receptor (NMDAR) and concomitant structural changes are essential for the initiation of long-term potentiation (LTP) and memory formation. Memories can be initiated by coincident events, as occurs in classical conditioning, where the NMDAR can act as a molecular coincidence detector. Binding of glutamate and glycine, together with depolarization of the postsynaptic cell membrane to remove the Mg²⁺ channel pore block, results in NMDAR opening for Ca²⁺ conductance. Accumulating evidence has implicated both force-from-lipids and protein tethering mechanisms for mechanosensory transduction in NMDAR, which has been demonstrated by both, membrane stretch and application of amphipathic molecules such as arachidonic acid (AA). The contribution of mechanosensitivity to memory formation and consolidation may be to increase activity of the NMDAR leading to facilitated memory formation. In this review we look back at the progress made toward understanding the physiological and pathological role of NMDA receptor channels in mechanobiology of the nervous system and consider these findings in like of their potential functional implications for memory formation. We examine recent studies identifying mechanisms of both NMDAR and other mechanosensitive channels and discuss functional implications including gain control of NMDA opening probability. Mechanobiology is a rapidly growing area of biology with many important implications for understanding form, function and pathology in the nervous system.

Keywords: NMDA; amygdala; force; learning; lipids; mechanobiology; memory.

FIGURE 1

Overall structure and activation mechanism of N-methyl-D-aspartate receptor (NMDAR) ion channel. (A) 3D structure of heterotetrameric NMDAR channel consisting of two GluN1a and two GluN2B subunits [adapted from Karakas and Furukawa (2014)]. Glycine and glutamate binding sites are indicated on the GluN1a and GluN2B subunits, respectively. Mg²⁺ binding site is represented by a dark blue circle. CTD refers to cytoplasmic domain. (B) Activation of NMDAR channel by insertion of an amphipathic molecule (e.g., arachidonic acid (AA) indicated by light blue rods) into the extracellular leaflet of the membrane bilayer (Casado and Ascher, 1998). One-sided insertion of AA is curving the bilayer, which changes the lateral pressure in the bilayer (black profile inset) causing the channel to open (Bavi O. et al., 2016).