Inhibition of glutamate release: a potential mechanism of action for the anticonvulsant U-54494A in the guinea pig hippocampus.
U-54494A, a 1,2-diamine, is a potent inhibitor of glutamate release in a synaptosomal preparation that is highly enriched with hippocampal mossy fiber (MF) nerve endings. At a concentration of 100 microM, U-54494A significantly reduced the availability of cytosolic free calcium (Ca2+) in depolarized MF-enriched synaptosomes by 30% and inhibited the K(+)-evoked release of endogenous glutamate by 85%. The extent to which glutamate release was inhibited allows us to conclude that U-54494A acts directly on the MF subpopulation of glutamatergic nerve endings in the guinea pig hippocampus. In addition, this anticonvulsant effectively countered the presynaptic facilitation of K(+)-evoked glutamate release that is induced by kainic acid (KA). Thus, while KA (1 mM) by itself nearly doubled the rate of K(+)-evoked glutamate release, there was no net increase in the presence of both KA and U-54494A (100 microM). However, the opposed effects of these two compounds on glutamate release do not appear to be due to a direct interaction. In the presence of U-54494A (100 microM), KA (1 mM) significantly enhanced the K(+)-evoked release of glutamate. Finally, it is demonstrated that the KA-induced enhancement of glutamate release does not require the depolarization-induced entry of extracellular Ca2+.
Conner-Kerr
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Department of Anatomy and Cell Biology, East Carolina University School of Medicine, Greenville, NC 27858.
Terrian
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D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001464:Barium / Q000378:metabolism; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003600:Cytosol / Q000502:physiology; D016257:Fura-2; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects* / Q000648:ultrastructure; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D010477:Perfusion; D011188:Potassium / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000187:drug effects / Q000648:ultrastructure; D013574:Synaptosomes / Q000187:drug effects
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D005971:Glutamates; D011759:Pyrrolidines; D001464:Barium; D018698:Glutamic Acid; D011189:Potassium Chloride; C054216:U 54494A; D011188:Potassium; D007608:Kainic Acid; D002118:Calcium; D016257:Fura-2