Human glutamate transport: Aspects of regulation



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Texas Tech University


Glutamate is the major excitatory neurotransmitter in the CNS including the retina. Termination of synaptic glutamate transmission and prevention of excitotoxicity depend on rapid removal of glutamate by neuronal and glial high affinity transporters. Molecular biological and pharmacological studies have demonstrated that at least four subtypes of sodium-dependent mammalian glutamate transporters exist. The following studies demonstrate that Y-79 human retinoblastoma cells express a single sodium-dependent glutamate uptake system with a Km of 1.7 ± 0.42 |LIM, that is inhibited by the glutamate uptake inhibitors dihydrokainate and DL-Threo-B-hydroxyaspartate. The protein kinase C activator phorbol 12- myristate 13-acetate caused a concentration-dependent inhibition of glutamate uptake (IC50 = 0.56 ± 0.05 nM). This inhibition resulted from a 5-fold decrease in the transporter's affinity for glutamate, without significantly altering its maximal velocity, and was blocked by pre treatment with the kinase inhibitor staurosporine.

The neuropeptide substance P produced a concentration-dependent inhibition of glutamate uptake (IC50 = 0.46 ± 0.14 nM). This inhibition is not mediated via any of the known tachykinin receptors. A strong inhibitory effect of glutamate uptake was also caused by the 25-35 amino acid fragment of beta-amyloid protein, the main component of the senile plaques found in the CNS of patients with Alzheimer's disease. The antagonist SR 142801 blocked both substance P's and beta-amyloid's inhibitory effects, suggesting that both peptides inhibit glutamate uptake via activation of the same site. A kinetic study shows that the inhibition of glutamate uptake caused by substance P resulted from a 75% reduction in the transporter's maximal velocity, without significantly altering its affinity for glutamate, indicating a mechanism other than protein kinase C activation.

These studies provide evidence for modulation of glutamate uptake by substance P via a novel site not coupled to the activation of protein kinase C. Beside having a physiological role in modulation of glutamatergic neurotransmission, this site may be involved in the pathophysiology of beta-amyloid protein.



Glutamates -- antagonists & inhibitors, Synaptic transmission, Protein kinase C, Neural transmission, Glutamates -- Physiology, Glutamates -- Physiological effect, Excitatory amino acids -- Receptors, Signal transduction, Retinoblastoma, Neurotransmitters