SLC1A4 is a gene in the human body that provides instructions for making a protein. This protein functions as a transporter, moving specific molecules across cell membranes. These membranes control what enters and exits the cell, and the SLC1A4 protein helps regulate this traffic.
The Role of SLC1A4 as a Transporter
The SLC1A4 gene codes for a protein known as Alanine/Serine/Cysteine/Threonine Transporter 1 (ASCT1). This protein serves as a sodium-dependent neutral amino acid transporter, moving specific amino acids like L-serine, L-alanine, L-cysteine, and L-threonine. Its main role is transporting L-serine, an amino acid with diverse roles in the body.
ASCT1 can move substances into or out of cells. For example, it takes up D-serine into astrocytes, a type of brain cell, and can also release L-serine from these cells through an exchange. This exchange supplies neurons with L-serine, which is then used to create D-serine. This movement of amino acids is powered by sodium ions.
SLC1A4’s Important Contributions to Body Systems
The transport activity of SLC1A4 contributes to many physiological processes, especially within the brain and muscle tissue. In the brain, SLC1A4 plays a role in neuronal development, neurotransmission, and overall brain metabolism. It helps regulate the levels of L-serine, which is necessary for the production of D-serine and glycine, both co-agonists for N-methyl-D-aspartate (NMDA) receptors.
NMDA receptors are important for synaptic plasticity, affecting learning and memory. SLC1A4 influences NMDA receptor activity by adjusting the D-serine available at synapses. It is also involved in the “serine shuttle,” transporting L-serine from astrocytes to neurons for D-serine synthesis.
Beyond the brain, SLC1A4 is present in other tissues like skeletal muscle, liver, kidney, and placenta. In skeletal muscle, L-serine is involved in energy metabolism and the synthesis of proteins and sphingolipids. The transport of amino acids by SLC1A4 supports processes like muscle growth and repair.
When SLC1A4 Function Goes Awry
When the SLC1A4 gene undergoes mutations or its function is impaired, it can lead to health issues, particularly affecting neurological development. This dysfunction can result in conditions like intellectual disability, microcephaly (a smaller-than-normal head size), epilepsy, spastic paraplegia, and developmental delays. These conditions arise because a malfunctioning SLC1A4 transporter disrupts the normal movement of specific amino acids.
Impaired transport of L-serine across the blood-brain barrier and within the brain itself leads to reduced L-serine levels, affecting the synthesis of compounds like D-serine. This disruption alters neurotransmitter precursor availability and neural signaling, contributing to the observed neurological problems. For instance, a decrease in D-serine can impair NMDA receptor activity, which is important for brain development and function. Studies have shown that mice lacking functional ASCT1, the protein encoded by SLC1A4, exhibit lower brain D-serine levels, along with motor and neurodevelopmental deficits.
Some mutations, such as the Glu256Lys mutation, are more prevalent in specific populations, like individuals of Ashkenazi Jewish ancestry, with a carrier rate of about 0.7%. These genetic changes can lead to conditions characterized by severe intellectual disability, progressive microcephaly, spasticity, and a thin corpus callosum, a part of the brain that connects the two hemispheres. The consequences of SLC1A4 dysfunction underscore the importance of amino acid transport for healthy brain development and function.