Arachidonic acid is released by phospholipase A2 when activation of N-methyl-D-aspartate (NMDA) receptors by neurotransmitter glutamate raises the calcium concentration in neurons, for example during the initiation of long-term potentiation and during brain anoxia. Here we investigate the effect of arachidonic acid on glutamate-gated ion channels by whole-cell clamping isolated cerebellar granule cells. Arachidonic acid potentiates, and makes more transient, the current through NMDA receptor channels, and slightly reduces the current through non-NMDA receptor channels. Potentiation of the NMDA receptor current results from an increase in channel open probability, with no change in open channel current. We observe potentiation even with saturating levels of agonist at the glutamate- and glycine-binding sites on these channels; it does not result from conversion of arachidonic acid to lipoxygenase or cyclooxygenase derivatives, or from activation of protein kinase C. Arachidonic acid may act by binding to a site on the NMDA receptor, or by modifying the receptor's lipid environment. Our results suggest that arachidonic acid released by activation of NMDA (or other) receptors will potentiate NMDA receptor currents, and thus amplify increases in intracellular calcium concentration caused by glutamate. This may explain why inhibition of phospholipase A2 blocks the induction of long-term potentiation.

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Neurotransmitter release from many central nervous system synapses is regulated by 'autoreceptors' at the synaptic terminal, which bind the released transmitter and alter release accordingly. The photoreceptors of lower vertebrates are thought to use glutamate as a neurotransmitter. Glutamate conveys the visual signal to postsynaptic bipolar and horizontal cells, but has been reported not to act on the photoreceptors themselves. We show here that glutamate evokes a current, carried largely by chloride ions, in cones isolated from the tiger salamander retina. This response is localized to the synaptic terminal of the cone. Removing external sodium blocks this action of glutamate. These results suggest the existence of a positive feedback loop at the cone output synapse: over most of the light-response range, glutamate released by depolarization of the cone will cause further depolarization, increasing the gain of phototransduction. Glutamate released from rods may also polarize cones, modulating the gain of the cone output synapse. This system is surprisingly different from the autoreceptor systems for most other transmitters, which act in a negative feedback way.

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