[3H]gabapentin may label a system-L-like neutral amino acid carrier in brain.
The ability of large neutral amino acids to interact with a site in mouse and pig brain labelled by [3H]gabapentin was examined. As previously described for rat tissue, [3H]gabapentin bound to synaptic plasma membranes prepared from mouse or pig cerebral cortex with high affinity (Kinetically derived KD = 14 and 17 nM for mouse and pig, respectively). Equilibrium binding in each species was inhibited by gabapentin and a range of large neutral amino acids. L-leucine (IC50 = 80 nM), L-isoleucine (IC50 = 72 nM), L-norleucine (IC50 = 40 nM) and L-methionine (IC50 = 50 nM) were the most potent of those tested. Binding was also inhibited by L-phenylalanine (IC50 = 380 nM), L-valine (IC50 = 310 nM) and the selective system-L substrate 2-amino-2-carboxy-bicycloheptane (IC50 = 420 nM) but not by the sodium-dependent System-A substrate methylaminoisobutyric acid. The presence of a submaximal concentration of leucine reduced [3H]gabapentin binding affinity but did not affect the maximum number of binding sites, suggesting a competitive interaction between leucine and the binding protein. The results suggest [3H]gabapentin may label a site in brain that resembles the large neutral amino acid transporter described in other tissues.
Thurlow
R J
RJ
Parke-Davis Neuroscience Research Centre, Addenbrookes Hospital Site, Cambridge, UK.
Brown
J P
JP
Gee
N S
NS
Hill
D R
DR
Woodruff
G N
GN
D000085:Acetates / Q000493:pharmacokinetics / Q000494:pharmacology*; D000588:Amines; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D066298:In Vitro Techniques; D051379:Mice; D011485:Protein Binding; D013552:Swine; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000596:Amino Acids; D002352:Carrier Proteins; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin