GNAS1

Overview

GLT-1, also known as the glutamate transporter 1 or EAAT2 (Excitatory Amino Acid Transporter 2), is a crucial protein in the central nervous system responsible for the uptake of the neurotransmitter glutamate from the synaptic cleft. This transporter plays a vital role in maintaining the extracellular glutamate concentration below neurotoxic levels, thus preventing excitotoxicity, which can lead to neuronal damage and death.

Structure

GLT-1 is a member of the solute carrier family 1 (SLC1), specifically the SLC1A2 gene in humans. It is a transmembrane protein that spans the cell membrane multiple times, forming a channel through which glutamate is transported. The protein is predominantly expressed in astrocytes, a type of glial cell in the brain, although it is also found in neurons to a lesser extent.

Function

The primary function of GLT-1 is to clear glutamate from the synaptic cleft after it has been released during neurotransmission. This process is essential for terminating the synaptic signal and preventing excessive activation of glutamate receptors, which can lead to excitotoxicity. GLT-1 operates by coupling the transport of glutamate with the co-transport of three sodium ions and one proton, and the counter-transport of one potassium ion, making it an electrogenic transporter.

Regulation

The expression and activity of GLT-1 are tightly regulated by various factors, including:

• Transcriptional regulation: Several transcription factors, such as NF-κB and AP-1, have been implicated in the regulation of GLT-1 expression.
• Post-translational modifications: Phosphorylation and ubiquitination can affect the stability and activity of GLT-1.
• Environmental factors: Conditions such as hypoxia, oxidative stress, and inflammation can modulate GLT-1 expression and function.

Clinical Significance

Dysfunction of GLT-1 has been implicated in several neurological disorders, including:

• Amyotrophic lateral sclerosis (ALS): Reduced GLT-1 expression and function have been observed in ALS, contributing to motor neuron degeneration.
• Epilepsy: Impaired glutamate uptake due to GLT-1 dysfunction can lead to increased excitability and seizure activity.
• Ischemic stroke: During ischemia, reduced GLT-1 activity can exacerbate neuronal damage due to excitotoxicity.

Research and Therapeutic Potential

Enhancing GLT-1 function is a potential therapeutic strategy for conditions associated with excitotoxicity. Various approaches, including pharmacological agents and gene therapy, are being explored to upregulate GLT-1 expression or activity.

Also see

• Glutamate receptor
• Excitotoxicity
• Astrocyte
• Neurotransmitter transporters