Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l-Glu, l-Asp and d-Asp, accompanied by the cotransport of 3 Na(+) and 1 H(+), and the countertransport of 1 K(+), whereas ASC transporters mediate Na(+)-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to "reversed glutamate transport", which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS.
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PMID:The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects. 1453 Sep 74

Efflux of glutamate from intracellular pools during hypoxia-ischemia has been postulated to be mediated by amino acid transporters and can lead to excitotoxicity. In addition, a decrease in pH seen during global hypoxia-ischemia may influence which transporter is responsible for this glutamate efflux. For example, the neutral amino acid transporter ASCT1 is an effective transporter of glutamate at low pH. We have examined the effects of pH, pH and temperature, and hypoxia on glutamate efflux in a rat primary neuronal cell culture model. We observed a marked increase of glutamate efflux as pH was decreased from 7.4 to 5.5. This pH-dependent efflux is likely due to a transporter-mediated process because it was seen in the presence of tetrodotoxin and was blunted by decreasing the temperature to either 35 degrees C or 33 degrees C. In addition, no increase in LDH was seen at pH 5.5 suggesting that increased glutamate levels were not due to cellular death. No change in glutamate levels was seen when the oxygen tension of the medium was lowered from 150 mm Hg to either 30 or 15 mm Hg. Given that EAAT transporters are inhibited by low pH, other transporters, such as ASCT1, may be responsible for this pH-dependent efflux of glutamate.
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PMID:A pH-dependent increase in neuronal glutamate efflux in vitro: possible involvement of ASCT1. 1612 9