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А series of the work „Modulation of secretory process by glutamate transporters and receptors”


Authors: Kasatkina L.A., Sivko R.V., Krupko O.O.

Glutamic acid is a major excitatory neurotransmitter in the mammalian central nervous system (CNS) that is implicated inthe process of recognition, memory, learning, etc. Prolonged elevation of glutamate concentration in the synaptic cleft leads to overstimulation of glutamate receptors, neurotoxicity and neuronal death, thereby underlying the development of many neurological diseases. Removal of glutamate from the synaptic cleft is mediated by high-affinity Na+- dependent glutamate transporters EAAT1 -5. Activation of glutamate receptors significantly modulates release of neurotransmitters, and so overall neurotransmission process. The role of glutamate as a regulatory molecule in peripheral tissues is poorly understood, although it is known that glutamate transporters and receptors are expressed in many types of the cell. So, the purpose of the work was to elucidate the mechanisms that are associated with the regulation of activity of glutamate transporters and presynaptic glutamate receptors, underlying   the modulation of the secretory process (exocytosis).

Experimental data uncover the mechanisms of modulation of high-affinity glutamate transporters functioning, which provide a high lability of the transport process depending on the lipid environment of the protein molecules, the plasma membrane potential and proton electrochemical gradient of synaptic vesicles. We have shown that activation of presynaptic glutamate receptors causes a two-stage release of GABA from nerve terminals of the cerebral cortex: the first stage is a synchronous exocytosis, stimulated by the increase in cytosolic Ca2+ concentration, and the second is prolonged asynchronous release of GABA after the Na+ influx through receptor-coupled ion channels.

Cholesterol is a potent endogenous modulator of activity of membrane proteins, in particular neurotransmitter transporters. It was shown that the reduction of membrane cholesterol content inhibits the exocytotic release of glutamate from nerve terminals and reduces the accumulation of glutamate in platelets. But under certain conditions (stroke, hypoxia, brain injury) reduction in membrane cholesterol content may have a neuroprotective effect and may explain the positive influence of statins (drugs that effectively reduce cholesterol level) under these conditions.

Comparative analysis of the active transport of glutamate in platelets and isolated brain nerve terminals shows the similarity of high-affinity Na+- dependent glutamate accumulation in platelets and isolated nerve terminals, but the mechanisms of glutamate release were significantly different. It has been shown that exocytosis is an exclusive way of glutamate release from platelets.

Experimentalresultsarepublishedin46 works, including 15 articles in peer-reviewed journals (including 14 cited in Scopus), 4 patents of Ukraine. Totalimpactfactoris41 according to Scopus Database. The author’s works are cited in 53 scientific articles.