Opposite modulation of NMDA receptors by lysophospholipids and arachidonic acid: common features with mechanosensitivity.

1. Two classes of amphiphilic compounds, lysophospholipids and arachidonic acid, have been suggested to produce opposite deformations of the lipid bilayer. We have found that their effects on N-methyl-D-aspartate (NMDA) responses are opposite, and resemble those of mechanical deformations of the plasma membrane. 2. Lysophospholipids inhibited NMDA responses both in nucleated patches taken from cultured neurons and in cells expressing recombinant NMDA receptors. This inhibition was reversible, voltage independent and stronger at non-saturating doses of agonist. It was not linked to the charge of the polar head, and was not mimicked by lysophosphatidic acid or phosphatidylcholine. In outside-out patches, lysophospholipids reduced the open probability of NMDA-activated channels without changing their single-channel conductance. 3. The inhibition produced by lysophospholipids occluded that produced by a mechanical compression induced by changes in osmotic or hydrostatic pressure. 4. The potentiation of NMDA responses by arachidonic acid was observed both in native and recombinant receptors, including those in which the putative 'fatty acid binding domain' had been deleted. This suggests that, like lysophospholipids, arachidonic acid alters the NMDA receptor by insertion into the lipid bilayer. 5. Recombinant receptors in which the cytoplasmic tails had been modified or deleted were still sensitive to mechanical deformation. A linkage to the cytoskeleton is therefore not required for NMDA receptor mechanosensitivity. 6. The fact that the NMDA responses are depressed similarly by compression and lysophospholipids, and potentiated similarly by stretch and arachidonic acid supports the notion that the modulation of NMDA receptor activity by asymmetrical amphiphilic compounds involves pressure changes transmitted through the lipid bilayer. Compounds with a large hydrophilic head mimic the effects of a compression, and compounds with a small hydrophilic head mimic the effects of stretch.