Selective Amino Acid Substitution Modifies Neurotransmitter Transporter Behavior

Researchers have identified the critical amino acids that comprise the site where the neurotransmitter creatine binds to the creatine transporter, the protein responsible for import of creatine into brain cells.

Creatine is a naturally occurring compound that is produced by the liver from the amino acids arginine and glycine. It is carried by the blood stream to the brain cells, as well as to the cells that make up the skeletal muscles, the heart, the retina, and various skin tissues.

In order to reach the brain, creatine must be successfully transported across the blood-brain barrier. The blood-brain barrier is a system specifically designed to facilitate the transport of needed metabolites to the brain neurons. In addition, by blocking their entry or facilitating their removal, the blood-brain barrier controls the presence of unnecessary metabolites or toxic substances in the brain.

When creatine reaches the blood-brain barrier, it is picked up by the creatine transporter, a member of a large family of sodium-dependent neurotransmitter and amino acid transporters, and moved across the endothelium into the brain tissues. In brain tissue, creatine is selected by the high affinity neuronal plasma membrane creatine transporter and transferred into the brain cells (neurons and glia cells). This transfer of creatine is one directional and occurs against a significant creatine concentration inside the neurons and glia cells.

Investigators at the University of Auckland (New Zealand) used the high-resolution structure of a prokaryotic homologue of the creatine transporter, LeuT, to design a study into this protein's fine structure. They reported in the May 25, 2007, issue of the Journal of Biological Chemistry that combinations of two or three amino acid substitutions at four selected positions resulted in the loss of creatine transport activity and gain of a specific gamma-aminobutyric acid (GABA) transport function. The gained GABA transport capability could be blocked using standard GABA inhibitors.

"This research is very exciting and should lead us to greater understanding of how neural signals are transmitted,” said Dr. David Christie, associate professor of biological sciences at the University of Auckland. "We are gradually learning more about the brain, how it works and regulates itself, and we hope that this knowledge can be translated to treat develop treatments for human neurodegenerative diseases.”


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