Creatine Transporter System
The body has a number of specific creatine transporter (CT) systems that are responsible for delivering creatine creatine to tissues where it is utilized by the creatine kinase (CK) system to generate cellular energy. Typically, these CT systems are made up of two separate creatine transporters:
- The plasma membrane creatine transporter; and
- The mitochondrial creatine transporter
One of the body's most critical CT systems is responsible for delivering Creatine from the blood stream to the brain cells. As such, this system plays a pivotal role in maintaining a constant supply of energy to the brain and therefore significantly contributes to proper brain function. An important feature of this CT system is the fact that it has an additional creatine transporter located at the blood-brain barrier (BBB).
A recently diagnosed genetic defect, termed Creatine Transporter Defect (CTD), prevents the transport of creatine into the brain cells. As a result, CTD has been associated with severe mental retardation, as well as epilepsy and autistic-like behavior.
How the system works
Creatine is a naturally occurring compound that is produced by the liver from 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 BBB. The BBB is a system of barriers specifically designed to facilitate the transport of needed metabolites to the brain neurons. In addition, the BBB is also responsible for controlling the presence of unnecessary metabolites or toxic substances in the brain. This is accomplished by blocking their entry or facilitating their removal. As such, the BBB is a highly sophisticated control system in charge of preserving the homeostasis of the brain.
As Creatine passes by the BBB via the blood stream, it is picked up by the BBB creatine transporter and shuttled across the endothelium into the brain tissues. From the brain tissue Creatine is then 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.
At this point, creatine is stored in the cytoplast of the neurons and glia cells, where it is readily available to be trans-phosphorylated by the CK system into phosphocreatine (PCr) for energy consumption inside the mitochondria. To mediate this process, the mitochondrial creatine transporter, which sits on the inner mitochondrial membrane, is called upon to transport the creatine from the cell's cytoplast to the mitochondria.
In patients with defective creatine transporter genes, creatine is noticeably absent from the brain. While creatine supplementation increases the body's level of creatine and phosphocreatine in the muscles, it is ineffective in treating those symptoms that result from a defective creatine transporter gene. In order to be effective in treating these patients, CTD therapies must be able to deliver creatine or analogs by other means to the brain cells.
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