A role for the arachidonic acid cascade in fast synaptic modulation: ion channels and transmitter uptake systems as target proteins.
Recent evidence indicates that arachidonic acid (AA) and its metabolites play a fast messenger role in synaptic modulation in the CNS. 12-Lipoxygenase derivatives are released by Aplysia sensory neurons in response to inhibitory transmitters and directly target a class of K+ channels, increasing the probability of their opening. In this way, hyperpolarization is achieved and action potentials are shortened, leading to synaptic depression. Other types of K+ channels in vertebrate excitable cells have been found to be sensitive to arachidonic acid, lipoxygenase products, and polyunsaturated fatty acids (PUFA). In the mammalian CNS, arachidonic acid is released upon stimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors. We found that arachidonic acid inhibits the rate of glutamate uptake in both neuronal synaptic terminals and astrocytes. Neither biotransformation nor membrane incorporation are required for arachidonic acid to exert this effect. The phenomenon, which is rapid and evident at low microM concentrations of AA, may involve a direct interaction with the glutamate transporter or its lipidic microenvironment on the outer side of the cell membrane. Polyunsaturated fatty acids mimic arachidonate with a rank of potency parallel to the degree of unsaturation. Since the effect of glutamate on the synapses is terminated by diffusion and uptake, a slowing of the termination process may potentiate glutamate synaptic efficacy. However, excessive extracellular accumulation of glutamate may lead to neurotoxicity.
Volterra
A
A
Center of Neuropharmacology, University of Milan, Italy.
Trotti
D
D
Cassutti
P
P
Tromba
C
C
Galimberti
R
R
Lecchi
P
P
Racagni
G
G
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
D005231:Fatty Acids, Unsaturated; D005971:Glutamates; D007473:Ion Channels; D018377:Neurotransmitter Agents; D016718:Arachidonic Acid; D018698:Glutamic Acid