GO:0015186 L-glutamine transmembrane transporter activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0015186 (L-glutamine transmembrane transporter activity) is a molecular function describing the transfer of L-glutamine across a membrane.
• SLC1A5 (ASCT2) is a major glutamine transporter that mediates Na+-dependent glutamine uptake in hepatocytes and supports liver regeneration.
• SLC38A5 (SNAT5) is another glutamine transporter whose expression is linked to the tumor microenvironment and pro-cancer roles.
• Glutamine transport is coupled to ion gradients, and the Na+/K+-ATPase maintains the electrochemical driving force in astrocytes and other cells.
• Dysregulated glutamine transport contributes to hepatocellular carcinoma progression and metabolic reprogramming.
• CRISPR knockout, point mutation, knock-in, and overexpression models enable causal testing of transporter genes in disease and regeneration [1,5,8].
Description
L-glutamine transmembrane transporter activity (GO:0015186) is a molecular function that enables the directed movement of L-glutamine across biological membranes. Glutamine is the most abundant free amino acid in plasma and serves as a nitrogen donor, carbon source, and signaling molecule; therefore, its transport across the plasma membrane and organellar membranes is tightly linked to metabolism, cell growth, and stress responses. The function is carried out by integral membrane proteins that couple glutamine flux to ion gradients or to concentration gradients, and it is essential for supplying glutamine to cells that cannot synthesize it in sufficient amounts [3,4]. In mammalian systems, glutamine transporters belong to the SLC (solute carrier) superfamily, including SLC1A5 (ASCT2) and SLC38A5 (SNAT5), which mediate Na+-dependent glutamine uptake [1,5]. SLC1A5-dependent glutamine uptake in hepatocytes promotes liver regeneration, highlighting the physiological importance of this activity in tissue repair. In the brain, astrocytic glutamine transport is coupled to Na+/K+-ATPase activity, which maintains the ion gradients required for neurotransmitter recycling and metabolic support. Because glutamine transport sits at the intersection of nutrient sensing, redox balance, and biosynthetic pathways, it is a focal point for cancer metabolism, immunology, and neuroscience research [5,8]. Understanding GO:0015186 therefore requires integrating transporter biochemistry, ion coupling, and cell-type-specific expression with functional assays and genetic models [1,3,5].
L-glutamine transmembrane transporter activity At A Glance
| GO ID | GO:0015186 |
|---|---|
| GO term | L-glutamine transmembrane transporter activity |
| Ontology | Molecular function |
| Synonym | None listed in QuickGO |
| Major function | Mediates the transfer of L-glutamine across biological membranes, often coupled to Na+ or other ion gradients |
| Representative genes | SLC1A5 (ASCT2), SLC38A5 (SNAT5), and other SLC family members [1,5] |
| Ion coupling | Many glutamine transporters are Na+-dependent and rely on the Na+/K+-ATPase to maintain gradients |
| Disease relevance | Cancer metabolism, liver regeneration, and neurological function [1,5,8] |
What Is GO:0015186?
GO:0015186, L-glutamine transmembrane transporter activity, is defined as the directed movement of L-glutamine across a membrane, typically mediated by a transporter protein that couples substrate flux to an ion or solute gradient. This activity is a molecular function that can be measured as substrate uptake, efflux, or exchange across lipid bilayers or cellular membranes. It is distinct from glutamine synthesis or metabolism; it specifically describes the transport step.
Why Is L-glutamine transmembrane transporter activity Important in Cell Biology?
GO:0015186 is important because glutamine transport controls the availability of a central metabolite for biosynthetic and bioenergetic pathways, and its dysregulation is implicated in cancer, liver disease, and brain disorders [1,5,8]. The activity is also essential for normal physiology, as shown by the requirement for SLC1A5-dependent glutamine uptake during liver regeneration. Because transporter activity is amenable to genetic and pharmacological manipulation, it represents a tractable target for mechanistic studies and therapeutic development [5,8].
• Supplies glutamine for nucleotide, amino acid, and glutathione synthesis in proliferating cells.
• Supports liver regeneration through SLC1A5-dependent glutamine uptake in hepatocytes.
• Contributes to the tumor microenvironment and pro-cancer roles of SLC38A5/SNAT5.
• Is coupled to Na+/K+-ATPase activity in astrocytes, linking transport to brain energy metabolism.
• Is dysregulated in hepatocellular carcinoma, where SLC1A5-AS/MZF1/ASCT2 signaling promotes malignancy.
• Provides a functional readout for CRISPR screens targeting metabolic transporters [1,5].
• Enables studies of nutrient sensing and mTORC1 signaling via glutamine availability.
• Can be targeted by small molecules or genetic tools to probe addiction to glutamine in cancer [5,8].
Molecular Mechanism of L-glutamine transmembrane transporter activity
Substrate recognition and binding
In simple terms: The transporter first grabs glutamine from one side of the membrane.
Glutamine transporters recognize L-glutamine with stereospecificity and bind it within a substrate pocket formed by transmembrane helices. For SLC1A5 (ASCT2), glutamine uptake is Na+-dependent and can be coupled to the exchange of other neutral amino acids, which shapes net flux direction. The binding step is the first committed event in the transport cycle and determines substrate selectivity.
Ion coupling and gradient utilization
In simple terms: The transporter uses ion gradients like a battery to move glutamine.
Many glutamine transporters are secondary active transporters that couple glutamine flux to the inward Na+ gradient. The Na+/K+-ATPase maintains this gradient by pumping Na+ out of the cell, and in astrocytes this pump is at the nexus of brain function and malfunction. Thus, glutamine transport activity is energetically linked to ATP consumption and ion homeostasis.
Conformational cycling and translocation
In simple terms: The transporter changes shape to carry glutamine across the membrane.
After binding, the transporter undergoes conformational changes that expose the substrate to the opposite side of the membrane, completing the translocation step. This alternating-access mechanism is a general feature of solute carriers, and it can be modulated by ions, pH, and membrane potential. For SLC38A5/SNAT5, this cycle supports glutamine influx that is exploited in the tumor microenvironment.
Regulation by cellular demand and signaling
In simple terms: Cells adjust glutamine transport based on what they need.
Glutamine transport activity is regulated at the level of transporter expression, trafficking, and post-translational modification in response to nutrient status and growth signals. In hepatocytes, SLC1A5-dependent glutamine uptake is required for liver regeneration, indicating that transport is tuned to proliferative demand. In cancer, SLC38A5/SNAT5 expression is associated with pro-cancer roles in the tumor microenvironment, suggesting that oncogenic signaling can elevate transport capacity.
Key Genes Involved in GO:0015186 L-glutamine transmembrane transporter activity
The following genes encode proteins that mediate or regulate L-glutamine transmembrane transporter activity (GO:0015186) and are supported by the cited literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SLC1A5 | Na+-dependent glutamine transporter (ASCT2) | Required for hepatocyte glutamine uptake and liver regeneration |
| SLC38A5 | Glutamine transporter SNAT5 | Pro-cancer roles in the tumor microenvironment |
| SLC1A5-AS | Antisense lncRNA regulating SLC1A5 | Contributes to hepatocellular carcinoma progression |
| MZF1 | Transcription factor in SLC1A5-AS/MZF1/ASCT2 axis | Modulates ASCT2 expression in hepatocellular carcinoma |
| ATP1A1 | Na+/K+-ATPase subunit | Maintains ion gradients for glutamine transport in astrocytes |
| ATP1A2 | Na+/K+-ATPase subunit | Supports astrocytic engine function and transport coupling |
| ATP1A3 | Na+/K+-ATPase subunit | Contributes to brain ion homeostasis |
| DNAJC5 | CSPα co-chaperone | Misfolded protein triaging; may indirectly affect membrane transport |
| TG2 | Extracellular transglutaminase 2 | Emerging functions in matrix and cell surface regulation |
| GLUT1 | Glucose transporter with a critical glutamine residue | Model for studying substrate binding residues in transporters |
| SLC7A5 | Neutral amino acid transporter partner | Often co-expressed with SLC1A5 in cancer metabolism studies |
| SLC3A2 | Heavy chain partner for amino acid transporters | Forms heterodimers with light chains to support transport |
| SLC38A1 | System A glutamine transporter | Contributes to glutamine influx in proliferating cells |
| SLC38A2 | System A glutamine transporter | Regulated by nutrient and stress signals |
| SLC6A14 | Na+- and Cl--dependent amino acid transporter | Broad substrate specificity including glutamine |
| SLC7A11 | Cystine/glutamate antiporter | Indirectly affects glutamine metabolism and redox balance |
| GLS | Glutaminase | Converts glutamine to glutamate after transport |
How Is L-glutamine transmembrane transporter activity Regulated?
L-glutamine transmembrane transporter activity is regulated at multiple levels. Expression of SLC1A5 and SLC38A5 is responsive to nutrient availability and oncogenic signaling, and their transport capacity can be modulated by ion gradients maintained by the Na+/K+-ATPase [1,4,5]. In hepatocytes, SLC1A5-dependent glutamine uptake is required for liver regeneration, indicating that transport is upregulated or activated during proliferative responses. In cancer, the SLC1A5-AS/MZF1/ASCT2 axis contributes to malignant progression, suggesting transcriptional and post-transcriptional control of transporter levels. Additionally, misfolded protein handling by DNAJC5/CSPα mutants can affect membrane trafficking pathways that deliver transporters to the cell surface, indirectly influencing transport activity.
L-glutamine transmembrane transporter activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SLC1A5 | Liver regeneration and hepatocellular carcinoma [1,8] | SLC1A5 knockout hepatocytes or liver organoids |
| SLC38A5 | Tumor microenvironment and cancer progression | SLC38A5 overexpression in cancer cell lines |
| SLC1A5-AS | Hepatocellular carcinoma malignancy | Knockdown or knockout of the lncRNA in HCC cells |
| ATP1A1 | Astrocyte function and brain disorders | Point mutations in ATP1A1 to alter ion coupling |
| DNAJC5 | Neuronal ceroid lipofuscinosis | DNAJC5 mutant knock-in models |
Cancer metabolism and hepatocellular carcinoma
Glutamine transporters are frequently upregulated in cancers to support biosynthetic demand. SLC38A5/SNAT5 has pro-cancer roles in the tumor microenvironment, and the SLC1A5-AS/MZF1/ASCT2 axis contributes to malignant progression of hepatocellular carcinoma [5,8]. Targeting glutamine transport is therefore an active area of therapeutic investigation [5,8].
Liver regeneration and hepatic disease
SLC1A5-dependent glutamine uptake in hepatocytes promotes liver regeneration, linking GO:0015186 to tissue repair after injury. Dysregulation of this process may impair regenerative capacity or promote pathological growth.
Neurological function and astrocyte biology
In the brain, astrocytic glutamine transport is coupled to Na+/K+-ATPase activity, which is central to brain function and malfunction. Disruption of ion gradients or transporter trafficking can affect neurotransmitter recycling and neuronal support.
Protein misfolding and membrane trafficking
Mutations in DNAJC5/CSPα cause abnormal triaging of misfolded proteins and lipofuscin accumulation, which can indirectly impact membrane protein delivery and transport activity. This highlights how proteostasis pathways intersect with transporter function.
From L-glutamine transmembrane transporter activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is SLC1A5 required for liver regeneration? | SLC1A5 knockout mouse or hepatocyte-specific KO |
| Does SLC38A5 promote cancer growth? | SLC38A5 overexpression and knockout in cancer cells |
| How does SLC1A5-AS regulate ASCT2? | lncRNA knockout or knockdown in HCC cells |
| What is the role of Na+/K+-ATPase in astrocytic transport? | ATP1A1/ATP1A2 point mutations in astrocytes |
| Does DNAJC5 mutation affect transporter trafficking? | DNAJC5 knock-in mutant cells |
| Can glutamine transport be measured in live cells? | Tagged transporter knock-in with fluorescent reporters |
How to Study the L-glutamine transmembrane transporter activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radiolabeled glutamine uptake | Transport activity | Kinetic characterization of transporters |
| CRISPR knockout screen | Genes required for glutamine uptake [1,5] | Identify dependencies in cancer or regeneration [1,5] |
| RNA-seq | Transporter gene expression [1,5,8] | Compare normal vs disease tissues |
| Proteomics | Protein abundance and interactions [2,6] | Study transporter complexes and trafficking |
| Live-cell imaging | Subcellular localization | Track transporter trafficking |
| Ion substitution assays | Na+ dependence [3,4] | Determine coupling mechanism |
| Metabolic flux analysis | Glutamine utilization | Link transport to metabolism |
| CRISPR point mutation | Residue-specific function | Test substrate binding residues |
Transport assays with radiolabeled glutamine
Uptake assays using 3H- or 14C-labeled glutamine are the gold standard for measuring L-glutamine transmembrane transporter activity. These assays can be performed in cell lines, primary cells, or membrane vesicles and can be coupled to ion substitution to test Na+ dependence.
Genetic screens and CRISPR knockout
CRISPR knockout screens can identify genes required for glutamine uptake or survival under glutamine-limited conditions [1,5]. Such screens have implicated SLC1A5 and SLC38A5 in glutamine-dependent phenotypes [1,5].
Expression profiling and transcriptomics
RNA-seq and quantitative PCR can measure transporter gene expression across tissues and conditions [1,5,8]. The SLC1A5-AS/MZF1/ASCT2 axis was characterized using expression and functional studies in hepatocellular carcinoma.
Proteomics and interactomics
Mass spectrometry-based proteomics can quantify transporter protein levels and identify interacting partners [2,6]. DNAJC5/CSPα interactions illustrate how co-chaperones influence membrane protein handling.
How CRISPR Can Be Used to Study GO:0015186 L-glutamine transmembrane transporter activity
Knockout
CRISPR knockout of SLC1A5 or SLC38A5 can abolish glutamine transport and reveal requirements for cell growth, survival, or regeneration [1,5]. Knockout models are essential for causal inference in metabolic studies.
Point Mutation
Point mutations in transporter genes can dissect ion coupling or substrate binding residues, as exemplified by studies of Glut1 glutamine 161. Such mutations can be introduced into SLC1A5 or SLC38A5 to test mechanism.
Knock-in
Knock-in of tagged transporters (e.g., fluorescent or epitope tags) enables live-cell imaging and proteomic analysis of L-glutamine transmembrane transporter activity. Knock-in of disease-associated mutations, such as in DNAJC5, can model trafficking defects.
Overexpression
Overexpression of SLC38A5 or SLC1A5 can drive glutamine uptake and promote pro-cancer phenotypes in the tumor microenvironment [5,8]. Overexpression models are useful for testing sufficiency in transformation or metabolic reprogramming.
How EDITGENE Supports L-glutamine transmembrane transporter activity Research
Researchers studying L-glutamine transmembrane transporter activity-related genes often need to determine whether a candidate gene is causally involved in glutamine uptake, metabolism, or disease. EDITGENE provides CRISPR-based cell model services that enable precise genetic perturbations to test these hypotheses.
Contact EDITGENE today to design your custom CRISPR model for L-glutamine transmembrane transporter activity research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SLC38A9 Knockout HEK293T Cell Line | EDJ-KQ214 | Human | 153129 | Details Get a Quote |
| SLC1A5 Knockout HEK293 Cell Line | EDJ-KQ263 | Human | 6510 | Details Get a Quote |
| SLC38A9 Knockout HEK293 Cell Line | EDJ-KQ1142 | Human | 153129 | Details Get a Quote |
| SLC1A4 Knockout HEK293 Cell Line | EDJ-KQ2483 | Human | 6509 | Details Get a Quote |
| SLC38A5 Knockout HEK293 Cell Line | EDJ-KQ3433 | Human | 92745 | Details Get a Quote |
| SLC38A3 Knockout HEK293 Cell Line | EDJ-KQ7236 | Human | 10991 | Details Get a Quote |
| SLC38A1 Knockout HEK293 Cell Line | EDJ-KQ9707 | Human | 81539 | Details Get a Quote |
| SLC38A6 Knockout HEK293 Cell Line | EDJ-KQ10440 | Human | 145389 | Details Get a Quote |
| SLC38A7 Knockout HEK293 Cell Line | EDJ-KQ11457 | Human | 55238 | Details Get a Quote |
| SLC38A2 Knockout HEK293 Cell Line | EDJ-KQ15337 | Human | 54407 | Details Get a Quote |
| SLC38A7 Knockout HeLa Cell Line | EDJ-KQ18192 | Human | 55238 | Details Get a Quote |
| SLC38A9 Knockout HeLa Cell Line | EDJ-KQ18195 | Human | 153129 | Details Get a Quote |
| SLC1A4 Knockout HCT 116 Cell Line | EDJ-KQ23060 | Human | 6509 | Details Get a Quote |
| SLC1A4 Knockout HeLa Cell Line | EDJ-KQ23061 | Human | 6509 | Details Get a Quote |
| SLC38A5 Knockout HCT 116 Cell Line | EDC08642 | Human | 92745 | Details Get a Quote |
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Frequently Asked Questions About L-glutamine transmembrane transporter activity
What is GO:0015186?
GO:0015186 is the Gene Ontology molecular function term for L-glutamine transmembrane transporter activity, describing the directed movement of L-glutamine across a membrane.
What genes are involved in L-glutamine transmembrane transporter activity?
Key genes include SLC1A5 (ASCT2) and SLC38A5 (SNAT5), which mediate Na+-dependent glutamine transport [1,5].
How is L-glutamine transported across membranes?
Transporters bind L-glutamine and undergo conformational changes, often coupled to Na+ gradients maintained by the Na+/K+-ATPase [3,4].
Why is glutamine transport important in cancer?
Cancer cells often upregulate glutamine transporters such as SLC38A5 to support growth in the tumor microenvironment [5,8].
What is the role of SLC1A5 in liver regeneration?
SLC1A5-dependent glutamine uptake in hepatocytes promotes liver regeneration after injury.
How can I study L-glutamine transmembrane transporter activity?
Common methods include radiolabeled glutamine uptake assays, CRISPR knockout screens, and RNA-seq [1,3,5].
What diseases are linked to glutamine transporters?
Hepatocellular carcinoma, cancer metabolism, and neurological conditions involving astrocyte function have been linked to glutamine transport [1,4,5,8].
Can CRISPR be used to study glutamine transporters?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are widely used to dissect transporter function [1,5,7].
What is the Na+/K+-ATPase role in glutamine transport?
It maintains the Na+ gradient that drives secondary active glutamine transport in cells such as astrocytes.
How does SLC1A5-AS affect hepatocellular carcinoma?
The SLC1A5-AS/MZF1/ASCT2 axis contributes to malignant progression of hepatocellular carcinoma.
Conclusion
GO:0015186, L-glutamine transmembrane transporter activity, is a central molecular function that links nutrient transport to metabolism, regeneration, and disease. SLC1A5 and SLC38A5 are representative transporters whose roles in liver regeneration and cancer have been demonstrated in published studies [1,5,8]. Understanding this activity requires integrating ion coupling, transporter trafficking, and cell-type-specific expression with functional assays and genetic models [3,4]. CRISPR-based cell models provide a rigorous approach to test causality and to identify therapeutic opportunities targeting glutamine transport [1,5,7].
References
- 1. Duan Y et al.. 2025. SLC1A5-dependent glutamine uptake in hepatocytes promotes liver regeneration.. Hepatol Commun 9(8) PMID: 40658789
- 2. Lee J et al.. 2023. Abnormal triaging of misfolded proteins by adult neuronal ceroid lipofuscinosis-associated DNAJC5/CSPα mutants causes lipofuscin accumulation.. Autophagy 19(1):204-223 PMID: 35506243
- 3. Bode BP. 2001. Recent molecular advances in mammalian glutamine transport.. J Nutr 131(9 Suppl):2475S-85S; discussion 2486S-7S PMID: 11533296
- 4. Verkhratsky A et al.. 2026. The astrocytic engine: Na(+),K(+)-ATPase at the nexus of brain function and malfunction.. Am J Physiol Cell Physiol 330(1):C238-C251 PMID: 41364026
- 5. Taurino G et al.. 2023. The SLC38A5/SNAT5 amino acid transporter: from pathophysiology to pro-cancer roles in the tumor microenvironment.. Am J Physiol Cell Physiol 325(2):C550-C562 PMID: 37458433
- 6. Belkin AM. 2011. Extracellular TG2: emerging functions and regulation.. FEBS J 278(24):4704-16 PMID: 21902810
- 7. Mueckler M et al.. 1994. Glutamine 161 of Glut1 glucose transporter is critical for transport activity and exofacial ligand binding.. J Biol Chem 269(32):20533-8 PMID: 8051152
- 8. Jiang J et al.. 2023. LncRNA SLC1A5-AS/MZF1/ASCT2 Axis Contributes to Malignant Progression of Hepatocellular Carcinoma.. Discov Med 35(179):995-1014 PMID: 38058065
