Glutamate Transport System in the Spinal Cord: New Mechanistic Targets for Pharmacological Modulation of Excitatory Signalling

Gegelashvili, Georgi (2017) Glutamate Transport System in the Spinal Cord: New Mechanistic Targets for Pharmacological Modulation of Excitatory Signalling. The FEBS Journal, 284 (Sp1). pp. 151-152.

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Abstract

High-affinity glutamate transporters, GluTs (GLAST / EAAT1, GLT1 / EAAT2, EAAC1 / EAAT3, and EAAT4), as well as glutamate/cystine exchanger, xCT, are differentially expressed in sensory neurons, dorsal root ganglia (DRG) and surrounding glial cells in the spinal cord. Several pharmacological agents, believed to affect GluTs, including therapeutically promising beta-lactams, have been studied in co-cultures of DRG neurons and spinal glial cells, as well as tested in in vivo model of chronic pain. In such in vitro model system, that partially recapitulates primary pain signaling path, both glial and neuronal GluTs and xCT undergo expressional changes, as well as post-translational modifications. Thus, for the first time, altered expression of a rare splice variant, GLT1c, has been demonstrated, both in rat and human spinal astroglia. Direct signaling through GluTs, a phenomenon recently reported by us, was also found to be involved in the modulation of pain signaling. Thus, physiological doses of some pro-nociceptive agents (e.g. capsaicin, cytokines) activate caspases, that precisely cleave spinal GluTs at their cytoplasmic C-terminal domains, but do not cause cell death. Both truncated C-terminal domains and bioactive peptides produced by the caspase-dependent cleavage functionally interact with other cytoplasmic or nuclear signaling complexes participating in aberrant pain signaling. For example, soluble C-terminal fragments of EAAT4 interfere with protein translation machinery via phosphorylation of PHAS1, and thus modulate quantity of active GluT molecules in DRG neurons. In case of GLAST, the modified C-terminus functionally interacts with the modulatory FXYD2/ gamma-subunit of Na+, K+ ATPase in spinal astrocytes and thus provides its targeting /anchoring to the cell surface. The elucidated bioactive agents and regulatory pathways affecting glutamate signaling in the spinal cord can thus emerge as prospective drug prototypes/therapeutic targets

Item Type: Article
Uncontrolled Keywords: Glutamate transport; Signal Transduction; EAAT; DRG; Spinal cord; xCT; FXYD2
Subjects: Q Science > QW Biochemistry
Q Science > QY Biophysics
Q Science > QG Life Sciences
Q Science > Molecular Biosciences
Q Science > QF Neurobiology
Q Science > QI Neuroscience
Q Science > Q Science (General)
Q Science > QD Chemistry
Q Science > QO Biology
Q Science > QP Physiology
R Medicine > RB Pathology
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RZ Other systems of medicine
Depositing User: პროფესორი გიორგი (გოგი) გეგელაშვილი
Date Deposited: 20 Oct 2017 08:08
Last Modified: 20 Oct 2017 08:08
URI: http://eprints.iliauni.edu.ge/id/eprint/7112

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