Activity at the GABA transporter contributes to acute cellular swelling produced by metabolic impairment in retina.
The role of the GABA transporter in acute toxicity in chick retina due to metabolic inhibition was investigated by the use of several substrate (nipecotic acid, THPO) and nonsubstrate (SKF 89976A, NO711) GABA transport inhibitors. Metabolic stress-induced acute toxicity in the retina is characterized by swelling of distinct populations of retinal neurons and selective release of GABA into the medium. Inhibitor concentrations were based on that needed to attenuate 14C-GABA uptake at its approximate KM concentration by > or = 70%. Under basal conditions, substrate, but not nonsubstrate, inhibitors increased extracellular GABA, but did not cause histological swelling per se. Under conditions of glycolytic inhibition, nonsubstrate, but not substrate, inhibitors significantly attenuated acute toxicity. Metabolic stress-induced acute toxicity was not altered by the GABA agonist muscimol, nor did muscimol reverse the protective effects of nonsubstrate transport inhibitors, suggesting that an increase in extracellular GABA during metabolic stress was not a component of the acute phase of toxicity. The results indicate that during metabolic inhibition, activity at the GABA transporter contributes to acute cellular swelling.
Zeevalk
G D
GD
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Department of Neurology, Piscataway 08854, USA.
Nicklas
W J
WJ
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002642:Chick Embryo; D046508:Culture Techniques; D018755:GABA Agonists; D018756:GABA Antagonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins; D006019:Glycolysis; D007461:Iodoacetates; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D007555:Isoxazoles / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D026901:Membrane Transport Proteins; D009118:Muscimol; D009557:Nipecotic Acids / Q000494:pharmacology*; D027361:Organic Anion Transporters; D010091:Oximes / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives*; D012160:Retina / Q000378:metabolism* / Q000473:pathology / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D018755:GABA Agonists; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D007461:Iodoacetates; D007555:Isoxazoles; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; D010091:Oximes; C078793:NNC 711; C030278:nipecotic acid; D009118:Muscimol; C026804:4,5,6,7-tetrahydroisoxazolo(4,5-c)pyridin-3-ol; D005680:gamma-Aminobutyric Acid; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid; D011392:Proline; C010983:homoproline