Functional Cross-Talk Between Different Systems ofGlutamate Transport and Metabolism in the Spinal Cord

Gegelashvili, Georgi and Bjerrum, Ole Jannik (2015) Functional Cross-Talk Between Different Systems ofGlutamate Transport and Metabolism in the Spinal Cord. In: Glia Amino Acid Transporters in Health and Disease, 2015, Atlanta, Georgia.

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Neurons sensing noxious stimuli and conduct pain signals from periphery to the spinal cord are predominantly glutamatergic. Members of the SLC1A family of high-affinity glutamate transporters, GluTs (GLAST/EAAT1, GLT1 / EAAT2, EAAC1 / EAAT3, and EAAT4) are differentially expressed in sensory neurons and surrounding glial cells. These plasma membrane proteins together with glutamate/cystine exchanger, xCT, are responsible for fine tuning of glutamate concentrations at glutamate receptors and, thus, modulation of excitatory signalling in the spinal cord. Several compounds, believed to affect high-affinity glutamate transport system, including therapeutically promising beta-lactams, have been examined in an in vivo model of neuropathic pain. Both pain behavior and glutamate transporter expression have been investigated in this model at various time-points. For the first time, changes in the expression of rare splice variants of glial glutamate transporter GLT1 have been demonstrated in rats with induced neuropathic pain. The dynamics of expression of high-affinity glutamate transporter subtypes and pattern of nociceptive pointed at complex relations between the functional state of glutamate transport system and the levels of analgesia provided by the tested compounds. The glutamate transport system has been also studied in co-cultures of dorsal root ganglion (DRG) neurons and spinal glial cells. In this in vitro model system, that partially recapitulates primary pain signaling path, both glial and neuronal glutamate carrier proteins undergo changes in expression, as well as post-translational modifications, including proteolytic truncation. Such regulated cleavage depends on phosphorylation state of intracellular domains of glutamate carrier proteins. These functional modifications alter cell surface targeting of glutamate transporters, as well as elicit downstream signaling. This also affects GluT interaction with other components of the glutamate sensing- and metabolizing machinery, including mechanisms of refilling and recycling of synaptic vesicles in DRG neurons and spinal glia. The elucidated regulatory pathways seem to provide fine tuning of excitatory signaling in the spinal cord and, can, thus, emerge as prospective drug targets for chronic pain treatment. Our recent data indicate that one of the direct modes of transporter signaling is triggered by cell death-associated proteases, caspases. Low sublethal doses of some of pro-apoptosis agents (e.g. Alzheimer’s beta-amyloid, glutamate receptor ligands, cytokines) activate caspases, that cleave glutamate transporters GLAST, GLT1, EAAC1 and EAAT4 at their cytoplasmic C- or N-terminal domains.. Such an unusual signaling via glutamate transporters is mediated both by functionally modified, truncated C-terminal domains and by bioactive peptides that are produced by the caspase-dependent cleavage. These soluble peptides contain several short conserved motifs that functionally interact with other cytoplasmic, mitochondrial or nuclear signaling complexes. The truncation of EAAC1 produces peptides that contain PDZ domain-binding motif, as well as a stretch of 8 aa residues present in 82-FIP, a novel RNA- binding protein that also interacts with FMRP, fragile X mental retardation protein. Soluble C-terminal fragments of EAAT4 could also interfere with protein translation machinery via phosphorylation of PHAS1. In case of GLAST, the C-terminus is a component of a cytoplasmic scaffolding complex interacting with FXYD2/γ subunit of Na+, K+ ATPase. Glutamate-induced activation of GLAST recruits to the cell surface more transporter molecules that are complexed with FXYD2/ γ subunit and, thus, activates the astroglial sodium pump, presumably due to the modulatory effect of γ subunit on the kinetic parameters of the catalytic α-subunit of Na+,K+ ATPase. Thus, neurotransmitter transporters, that represent novel targets for caspases, can act as scaffolding / shuttle proteins and are capable of exhibiting receptor-like, signal-transducing properties, that could possibly affect neuronal function in some neurological and cognitive disorders, such as brain ischemia, ALS, or Alzheimer’s disease.

Item Type: Conference or Workshop Item (Paper)
Uncontrolled Keywords: Glutamate transport; Glutamate metabolism; Spinal cord; Signal transduction; Neurotrophins; Growth factors; Clavulanic acid; Ceftriaxone; beta-lactams; Pain; GluT; EAAT4; GLT-1; GLAST; EAAC1; EAAT3; xCT; Neuron-Glia interaction
Subjects: Q Science > QW Biochemistry
Q Science > QY Biophysics
Q Science > QG Life Sciences
R Medicine > RH Mental Health
Q Science > Molecular Biosciences
Q Science > QF Neurobiology
Q Science > QO Biology
Q Science > QP Physiology
R Medicine > RB Pathology
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RW Biopharmacy
Divisions: Institutes > Institute of Chemical Biology
Depositing User: პროფესორი გიორგი (გოგი) გეგელაშვილი
Date Deposited: 11 Oct 2017 08:15
Last Modified: 11 Oct 2017 08:15

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