Inhibition of phosphoinositide hydrolysis by the novel neurotoxin beta-N-oxalyl-L-alpha, beta-diaminopropionic acid (L-BOAA).
Inhibition by a recently isolated neurotoxic amino acid, beta-N-oxalyl-L-alpha, beta-diaminopropionic acid, (L-BOAA), of stimulated phosphoinositide hydrolysis was studied in rat brain cerebral cortical slices. L-BOAA inhibited the norepinephrine-stimulated response but did not affect hydrolysis induced by 55 mM K+, carbachol, or carbachol in the presence of 20 mM K+. The inhibition was concentration-dependent with an IC50 of 300 microM. This inhibition was insensitive to the excitatory amino acid antagonists, gamma-glutamylglycine, glutamic acid diethyl ether, CNQX, AP-4, AP-7, or kynurenate. Thus, we propose that the L-BOAA-mediated inhibition of the norepinephrine-stimulated response was due to an interaction at a novel site, which may also be sensitive to quisqualate (see discussion). The mechanism of the inhibition is still unknown but was not prevented by inhibition of phospholipase A2 or polyamine synthesis and it was not affected by blockade of chloride channels. However, the presence of 20 mM K+ completely blocked the inhibitory effect of L-BOAA on norepinephrine-stimulated phosphoinositide hydrolysis.
Ormandy
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Department of Pharmacology, University of Alabama, Birmingham 35294.
Jope
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D000409:Alanine / Q000031:analogs & derivatives*; D000599:Amino Acids, Diamino; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000633:toxicity
D000599:Amino Acids, Diamino; D009498:Neurotoxins; D010716:Phosphatidylinositols; D015091:beta-Alanine; C100126:oxalyldiaminopropionic acid; D000409:Alanine