Selective up-regulation of the glial Na+-dependent glutamate transporter GLT1 by a neuroimmunophilin ligand results in neuroprotection.
Excessive accumulation of extracellular glutamate results in neuronal death. Termination of synaptic glutamate transmission and the prevention of excitotoxicity depend on rapid removal of glutamate by high affinity Na+-dependent transporters. The astroglial transporter GLT1 is the predominant subtype, responsible for the bulk of extracellular clearance and for limiting excitotoxicity. This protein is crucial in the prevention of chronic glutamate neurotoxicity, and is markedly decreased in amyotrophic lateral sclerosis (ALS). Recent studies have shown that GLT1 expression can be induced in vitro and in vivo by various factors, but little is known about the signaling pathways mediating its regulation. The FK506-binding protein (FKBP) immunophilins are ubiquitous cytosolic proteins, concentrated in neural tissue (neuroimmunophilins). GPI-1046 is a synthetic, nonimmunosuppressive derivative of FK506 shown to exert neuroprotective and neuroregenerative actions in several systems. In the present study, we demonstrated that GPI-1046 induces selective expression of GLT1 in vitro and in vivo, associated with a marked increase in DHK-sensitive Na+-dependent glutamate transport. Furthermore, treatment with GPI-1046 was shown to protect motor neurons in an in vitro model of chronic excitotoxicity, and to prolong the survival of transgenic ALS mice. These studies suggest that neuroimmunophilins can regulate GLT1 and that their ligands could serve as therapies for neurodegenerative disorders.
Ganel
Raquelli
R
Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
Ho
Tony
T
Maragakis
Nicholas J
NJ
Jackson
Mandy
M
Steiner
Joseph P
JP
Rothstein
Jeffrey D
JD
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015151:Immunoblotting; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D015854:Up-Regulation
D027342:Excitatory Amino Acid Transporter 2; C104949:GPI 1046; D008024:Ligands; D018696:Neuroprotective Agents; D011759:Pyrrolidines; D022021:Tacrolimus Binding Proteins