INHIBITORY ACTIVITY OF A NATURALLY-OCCURRING HETEROCYCLIC BETA-SUBSTITUTED ALANINE, BETA-(ISOXAZOLIN-5-ON-4-YL)-L-ALANINE, ON THE L-GLUTAMATE L-ASPARTATE TRANSPORTER (GLAST) EXPRESSED IN XENOPUS OOCYTES/
K. Kusamaeguchi et al., INHIBITORY ACTIVITY OF A NATURALLY-OCCURRING HETEROCYCLIC BETA-SUBSTITUTED ALANINE, BETA-(ISOXAZOLIN-5-ON-4-YL)-L-ALANINE, ON THE L-GLUTAMATE L-ASPARTATE TRANSPORTER (GLAST) EXPRESSED IN XENOPUS OOCYTES/, Molecular brain research, 52(1), 1997, pp. 166-169
Excitatory amino acid (EAA) transporters are of physiological importan
ce in the regulation of the extracellular concentration of excitatory
amino acids and the neuroexcitation in CNS. Among four identified tran
sporters, the Na+-dependent high-affinity L-glutamate/L-aspartate tran
sporter (GLAST) is highly expressed in glial cells. Here, we report a
naturally occurring inhibitor of GLAST, derived from bovine retina, us
ing the Xenopus oocyte expression system. beta-(Isoxazolin-5-on-4-yl)-
L-alanine (TAN), an antifungal antibiotic, inhibited [C-14]L-glutamate
(L-Glu) transport into GLAST-expressing oocytes. TAN also served as a
substrate for this transporter in voltage-clamp experiments measuring
the current coupled to the EAA transport. The maximum current of TAN
itself was approximate to 1/3 of that of L-glutamate, and its apparent
affinity was almost the same as L-Glu. In combination with L-Glu, TAN
antagonized L-glutamate transport. In radioisotope experiments, the i
nhibitory potency of this compound against [C-14]L-Glu uptake into ooc
ytes was approximate to 1/6 of that of L-(-)-threo-3-hydroxyaspartate
(THA). The glucoside of TAN (TANG), occurring in seedlings of the gard
en pea, the lentil and some Lathyrus species, did not show any electro
physiological activity nor was it transported into oocytes. It is prop
osed that TAN is a novel type antagonist of natural origin on GLAST. B
y affecting such transport system, naturally occurring compounds may a
ffect the regulation of the extracellular level of endogenous EAA. (C)
1997 Elsevier Science B.V.