Reduced expression of astrocytic glycine transporter (Glyt-1) in acute liver failure.
A growing body of evidence suggests that alterations in N-methyl-D-asparate NMDA-mediated excitatory neurotransmission may be involved in the pathophysiology of hepatic encephalopathy (HE) in acute liver failure (ALF). The NMDA receptor requires glycine as a positive allosteric modulator. One of the glycine transporters Glyt-1 is expressed primarily in astrocytes of the cerebral cortex in association with regions of high NMDA receptor expression. As astrocytic transporters regulate the amino acid concentrations within excitatory synapses, the expression of Glyt-1 was studied in cortical preparations from rats with ischemic liver failure induced by portacaval anastomosis followed 24 hr later by hepatic artery ligation and from appropriate sham-operated controls. Expression of Glyt-1 mRNA, studied by reverse transcriptase-polymerase chain reaction, was significantly decreased in the brain at coma stages of encephalopathy (to approximately 50% of control) concomitant with a significant threefold increase of extracellular glycine, measured by in vivo cerebral microdialysis. These findings suggest that loss of expression of the Glyt-1 transporter may cause an impairment of regulation of glycine concentration at synaptic level and contribute to an overactivation of the NMDA receptor in ALF. The use of NMDA receptor antagonists, aimed specifically at the glycine modulatory site, could offer novel approaches to the prevention and treatment of HE in ALF.
Zwingmann
Claudia
C
Neuroscience Research Unit, CHUM Hôpital Saint-Luc, Montreal, Quebec, Canada.
Desjardins
Paul
P
Hazell
Alan
A
Chatauret
Nicolas
N
Michalak
Adriana
A
Butterworth
Roger F
RF
D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins; D017114:Liver Failure, Acute / Q000378:metabolism*; D008297:Male; D009994:Osmolar Concentration; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D026921:Amino Acid Transport Systems, Neutral; D050487:Glycine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; C493266:Slc6a9 protein, rat