TY - JOUR
T1 - Inhibition of the Phospholipase C‐Linked Metabotropic Glutamate Receptor by 2‐Amino‐3‐Phosphonopropionate Is Dependent on Extracellular Calcium
AU - Lonart, Gyorgy
AU - Alagarsamy, Sudarkodi
AU - Ravula, Radhika
AU - Wang, Jia
AU - Johnson, Kenneth M.
PY - 1992/8
Y1 - 1992/8
N2 - Abstract: D,L‐2‐Amino‐3‐phosphonopropionate (AP‐3), a proposed metabotropic receptor antagonist, produced a concentration‐dependent increase in the formation of inositol 1,4,5‐trisphosphate in rat hippocampal slices. The response was maximal at 1 mM and completely due to the l‐isomer. d,l‐AP‐3 was half as efficacious as (1S,3R)‐1‐aminocyclopentane‐1,3‐dicarboxylic acid (1S,3R‐ACPD), a selective agonist of this receptor. The response produced by maximally effective concentrations of l‐AP‐3 and 1S,3R‐ACPD together for 5 min was not significantly different from that produced by 1S,3R‐ACPD alone. However, pretreatment for 40 min with either 1 mM l‐AP‐3 or D,L‐AP‐3 completely inhibited the response to 1S,3R‐ACPD. This inhibition was long‐lasting (wash‐resistant) and was reversed by reduction of the extracellular Ca2+ concentration. Also, pretreatment for 40 min with 1S,3R‐ACPD reduced, but did not completely block, the response to readdition of 1S,3R‐ACPD. l‐AP‐3 (1 mM) also produced a stereoselective 2.3‐fold increase in the efflux of glutamate from the hippocampal slices. These data suggest that incubation of hippocampal slices with AP‐3 induces a time‐dependent desensitization of the metabotropic response by a mechanism that is dependent on extracellular Ca2+. The possible roles of receptor occupancy and inhibition of glutamate uptake by AP‐3 are also discussed.
AB - Abstract: D,L‐2‐Amino‐3‐phosphonopropionate (AP‐3), a proposed metabotropic receptor antagonist, produced a concentration‐dependent increase in the formation of inositol 1,4,5‐trisphosphate in rat hippocampal slices. The response was maximal at 1 mM and completely due to the l‐isomer. d,l‐AP‐3 was half as efficacious as (1S,3R)‐1‐aminocyclopentane‐1,3‐dicarboxylic acid (1S,3R‐ACPD), a selective agonist of this receptor. The response produced by maximally effective concentrations of l‐AP‐3 and 1S,3R‐ACPD together for 5 min was not significantly different from that produced by 1S,3R‐ACPD alone. However, pretreatment for 40 min with either 1 mM l‐AP‐3 or D,L‐AP‐3 completely inhibited the response to 1S,3R‐ACPD. This inhibition was long‐lasting (wash‐resistant) and was reversed by reduction of the extracellular Ca2+ concentration. Also, pretreatment for 40 min with 1S,3R‐ACPD reduced, but did not completely block, the response to readdition of 1S,3R‐ACPD. l‐AP‐3 (1 mM) also produced a stereoselective 2.3‐fold increase in the efflux of glutamate from the hippocampal slices. These data suggest that incubation of hippocampal slices with AP‐3 induces a time‐dependent desensitization of the metabotropic response by a mechanism that is dependent on extracellular Ca2+. The possible roles of receptor occupancy and inhibition of glutamate uptake by AP‐3 are also discussed.
KW - Desensitization
KW - Hippocampus
KW - Inositol 1,4,5‐trisphosphate
KW - d,l‐2‐Amino‐3‐phosphonopropionate
KW - trans‐D,L‐1‐Aminocyclopentane‐1,3‐dicarboxylic acid
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U2 - 10.1111/j.1471-4159.1992.tb09438.x
DO - 10.1111/j.1471-4159.1992.tb09438.x
M3 - Article
C2 - 1321236
AN - SCOPUS:0026755376
SN - 0022-3042
VL - 59
SP - 772
EP - 775
JO - Journal of neurochemistry
JF - Journal of neurochemistry
IS - 2
ER -