Triethyllead inhibits gamma-aminobutyric acid binding to uptake sites in synaptosomal membranes.
Triethyllead (TEL), the active metabolite of tetraethyllead, was shown previously to inhibit selectively high-affinity Na+-dependent uptake of gamma-aminobutyric acid (GABA) into cerebrocortical synaptosomes. Such inhibition was not related to the Na+ gradient, Na+,K+-ATPase activity, [Cl-], or energy charge. We report here that TEL inhibits GABA binding to the presynaptic transporter involved in Na+-dependent uptake. Scatchard plot analysis of Na+-dependent [3H]GABA binding to a highly purified synaptic plasma membrane preparation revealed that 25 microM TEL reduced the Bmax by 44%, leaving the KD unchanged. This binding was reversible and predominantly involved membrane uptake sites, as characterized by pharmacological specificity to GABA ligands. Approximately 85% of specific GABA binding was considered membrane uptake site binding, as indicated by sensitivity to nipecotic acid and diaminobutyric acid, with relative insensitivity to muscimol, bicuculline methiodide, baclofen, and beta-alanine. With respect to previous data, these finding suggest that TEL inhibits Na+-sensitive high-affinity GABA uptake by interfering with GABA binding to its presynaptic transporter.
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D007425:Intracellular Membranes / Q000378:metabolism*; D007700:Kinetics; D009498:Neurotoxins / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D009498:Neurotoxins; D009942:Organometallic Compounds; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C010360:triethyllead