Role of ammonia in reversal of glutamate-mediated Müller cell swelling in the rat retina.
Glutamate is thought to participate in a variety of retinal degenerative disorders. However, when exposed to glutamate at concentrations up to 1 mM, ex vivo rat retinas typically exhibit Müller cell swelling, but not excitotoxic neuronal damage. This Müller cell swelling is reversible following glutamate washout, indicating that the glial edema is not required for glutamate-induced neuronal injury. It is unclear whether glutamate directly induces the Müller cell swelling or whether a metabolite of glutamate such as glutamine acts as an osmolyte to generate the cellular edema. To examine this issue, ex vivo rat retinas were exposed to 1 mM glutamate or 1 mM glutamine and were evaluated histologically. Glutamate was also combined with 1 mM ammonia or with methionine sulfoximine (MSO), an inhibitor of glutamine synthetase, the enzyme that catalyzes the synthesis of glutamine from glutamate and ammonia. Glutamate-mediated Müller cell swelling was blocked by co-administration of ammonia and the reversibility of Müller cell swelling was inhibited by MSO administered following glutamate exposure. Glutamine alone failed to induce Müller cell swelling. These results indicate that glutamate-mediated Müller cell swelling is unlikely to result from glutamine accumulation. Rather, conversion of glutamate to glutamine in a reaction involving ammonia helps reverse Müller cell swelling following exposure to exogenous glutamate.
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
Yukitoshi
Y
Izumi
Mio
M
Matsukawa
Ann M
AM
Benz
Masayo
M
Izumi
Makoto
M
Ishikawa
John W
JW
Olney
Charles F
CF
Zorumski
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000502:physiology; D048429:Cell Size / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors; D018698:Glutamic Acid / Q000378:metabolism / Q000502:physiology*; D005973:Glutamine / Q000378:metabolism; D007035:Hypothermia / Q000503:physiopathology; D008717:Methionine Sulfoximine / Q000494:pharmacology; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology*; D012164:Retinal Diseases / Q000503:physiopathology; D016707:Tissue Fixation
D018691:Excitatory Amino Acid Antagonists; D005973:Glutamine; D008717:Methionine Sulfoximine; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000641:Ammonia; D005974:Glutamate-Ammonia Ligase