Inhibition of the phospholipase C-linked metabotropic glutamate receptor by 2-amino-3-phosphonopropionate is dependent on extracellular calcium.
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.
Lonart
G
G
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031.
Alagarsamy
S
S
Ravula
R
R
Wang
J
J
Johnson
K M
KM
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000032:analysis / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D005109:Extracellular Matrix / Q000737:chemistry; D019204:GTP-Binding Proteins / Q000378:metabolism; D005971:Glutamates / Q000032:analysis / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism* / Q000502:physiology
D005971:Glutamates; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; C000211:2-amino-3-phosphonopropionic acid; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D000409:Alanine; D002118:Calcium