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Two Groups of Amino Acids Interact with GABA‐A Receptors Coupled to t ‐[ 35 S]Butylbicyclophosphorothionate Binding Sites: Possible Involvement with Seizures Associated with Hereditary Amino Acidemias
Author(s) -
Squires Richard F.,
Saederup Else,
Lajtha Abel
Publication year - 1988
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1988.tb01819.x
Subject(s) - amino acid , chemistry , stereochemistry , receptor , tryptamine , biochemistry
Seven L‐amino acids (Trp, Arg, Lys, Met, lie, Val, and Phe) partially (28–81%) reversed the inhibitory action of 1 μ M γ‐aminobutyric acid (GABA) on t ‐[ 35 S]‐butylbicyclophosphorothionate ([ 35 S]TBPS) binding to rat brain membranes, with EC 50 values ranging from 5 to 120 m M . d‐Trp, d‐Arg, d‐Lys, d‐Met, d‐Val, and d‐Phe were approximately equipotent with their L‐isomers. Tyramine, phenethylamine, and tryptamine, the decarboxylation products of the aromatic amino acids (Tyr, Phe, and Trp, respectively), reversed the inhibitory action of 1 μ M GABA on [ 35 S]TBPS binding more potently than the parent amino acids (EC 50 values = 1.5–3.0 mM). Human hereditary amino acidemias involving Arg, Lys, lle, Val, and Phe are associated with seizures, and these amino acids and/or their metabolites may block GABA‐A receptors. Five other L‐aminc acids (ornithine, His, Glu, Pro, and Ala) as well as Gly and β‐Ala inhibited [ 35 S]TBPS binding with IC 50 values ranging from 0.1 to 37 m M , and these inhibitions were reversed by the GABA‐A receptor blocker R 5135 in all cases. The inhibitory effects of l‐ornithine, l‐Ala, l‐Glu, and l‐Pro were stereospecific, because the corresponding d‐isomers were considerably less inhibitory. l‐His, d‐His, and l‐Glu gave incomplete (plateau) inhibitions. Human hereditary amino acidemias involving l‐ornithine, His, Pro, Gly, and β‐Ala are also associated with seizures, and we speculate that these GABA‐mimetic amino acids may desensitize GABA‐A receptors. l‐Asn, l‐Ser, l‐Thr, l‐Cys, l‐Asp, l‐Leu, and l‐Gln at 100 m M and l‐Tyr at 10 m M had no significant inhibitory effect on [ 35 S]TBPS binding, nor did they reverse the inhibitory effect of 1 μ M GABA. Amino acidemias involving the latter eight amino acids do not appear to be associated with seizures.