SLC7A3 — Cationic Amino Acid Transporter 3

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SLC7A3 — Cationic Amino Acid Transporter 3

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SLC7A3 — Cationic Amino Acid Transporter 3</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>SLC7A3</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Cationic Amino Acid Transporter 3 (CAT3)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>Xq28</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[6534](https://www.ncbi.nlm.nih.gov/gene/6534)</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[300443](https://www.omim.org/entry/300443)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000165370</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q8WWI5](https://www.uniprot.org/uniprot/Q8WWI5)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Overview

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SLC7A3 — Cationic Amino Acid Transporter 3

Overview

SLC7A3 (Solute Carrier Family 7 Member 3), also known as Cationic Amino Acid Transporter 3 (CAT3), is a human gene encoding a high-affinity cationic amino acid transporter protein. This transporter is primarily responsible for the uptake of cationic amino acids, particularly arginine and lysine, into cells. SLC7A3 is expressed predominantly in the developing and adult brain, where it plays critical roles in neuronal development, synaptic function, and nitric oxide (NO) signaling[@ito1997][@closs2001]. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

Molecular Function

Cationic Amino Acid Transport

SLC7A3 encodes a member of the system y+ family of cationic amino acid transporters[cat1_function2010]. The transporter exhibits high affinity for cationic amino acids:

Substrate Specificity: CAT3 primarily transports:

L-Arginine (highest affinity)
L-Lysine
L-Ornithine
L-Histidine (lower affinity)

Transport Properties: CAT3 is a Na+-independent transporter that operates as an antiporter, exchanging intracellular amino acids for extracellular cationic amino acids. The transporter has a high affinity (Km ~ 50-100 μM) for its substrates, making it important for cellular uptake under physiological conditions[closs2001].

System y+ Transport

The SLC7 family includes multiple cationic amino acid transporters (CAT1-4), each with distinct expression patterns and functional properties[system_y_plus2012]:

SLC7A1 (CAT1): Widely expressed, essential for vascular arginine transport
SLC7A2 (CAT2): Inducible, important in inflammation
SLC7A3 (CAT3): Neuron-specific, high-affinity arginine transporter
SLC7A4 (CAT4): Lower affinity, broader substrate range

Role in Nitric Oxide Synthesis

One of the most important functions of CAT3 in the brain is providing arginine substrate for nitric oxide synthase (NOS)[hatanaka2008]:

Nitric Oxide Signaling: Arginine is the sole substrate for nitric oxide synthesis by neuronal nitric oxide synthase (nNOS). CAT3-mediated arginine uptake is therefore essential for NO production in neurons.

nNOS Activation: Neuronal activity triggers nNOS activation, which requires rapid arginine replenishment. CAT3's high-affinity transport ensures adequate substrate availability during signaling events[nakamura2017].

NO Functions in the Brain: Nitric oxide serves as a:

Neurotransmitter/neuromodulator
Regulator of cerebral blood flow
Mediator of synaptic plasticity
Second messenger in learning and memory

Role in Brain Development

Developmental Expression

SLC7A3 is highly expressed during brain development, particularly in neuronal populations[hosokawa2002][@kikuchi2013]:

Embryonic Expression: During embryogenesis, CAT3 is expressed in neural progenitor cells and newly differentiated neurons. The transporter appears early in development and peaks during periods of active neurogenesis.

Postnatal Development: SLC7A3 expression continues to increase postnatally, corresponding to:

Synaptogenesis
Dendritic arborization
Myelination

Adult Expression: In the adult brain, SLC7A3 is expressed in specific neuronal populations, particularly in the [hippocampus](/brain-regions/hippocampus), [cortex](/brain-regions/cortex), and [cerebellum](/brain-regions/cerebellum)[@vekhi2002].

Neuronal Differentiation

CAT3 plays a role in neuronal differentiation through several mechanisms[agarwal2014]:

Arginine Availability: Adequate intracellular arginine is required for:

Protein synthesis during neurite outgrowth
Polyamine synthesis (putrescine, spermidine, spermine)
Nitric oxide signaling during differentiation

Metabolic Programming: Arginine metabolism influences the metabolic state of developing neurons, affecting their survival and differentiation potential.

Brain Patterning

Studies in knockout mice have revealed important roles for SLC7A3 in brain development[stork2005]:

Normal cortical layering
Hippocampal formation
Cerebellar development
Axonal tract development

Expression Pattern

Regional Distribution

SLC7A3 shows region-specific expression in the brain[vekhi2002]:

Hippocampus: High expression in CA1-CA3 pyramidal neurons and dentate gyrus granule cells. The hippocampus shows some of the highest SLC7A3 expression in the adult brain.

Cortex: Expression in pyramidal neurons across all cortical layers, with highest levels in layer V neurons that project to subcortical structures.

Cerebellum: Expression in Purkinje cells and granule cells. The transporter is particularly important in cerebellar development.

Brainstem: Expression in various nuclei including the dorsal raphe (serotonergic) and locus coeruleus (noradrenergic).

Cellular Localization

Within neurons, CAT3 is localized to:

Soma: Cell body membrane
Dendrites: Dendritic shaft and spine membranes
Axon terminals: Presynaptic membranes
Endoplasmic reticulum: Intracellular pool

This subcellular distribution supports roles in synaptic function and dendritic arginine metabolism.

Disease Associations

Alzheimer's Disease

Arginine metabolism is increasingly recognized as relevant to Alzheimer's disease pathogenesis[ad_arginine2018]:

Arginine Depletion: AD brains show altered arginine metabolism, with decreased arginine availability in neurons. This may reflect reduced CAT3 function or expression.

nNOS Dysfunction: Nitric oxide signaling is impaired in AD, partly due to substrate limitation. CAT3 dysfunction could contribute to reduced NO production and impaired synaptic plasticity.

Polyamine Metabolism: The polyamine pathway is altered in AD. Since arginine is a precursor for polyamines, CAT3 dysfunction may affect this important metabolic pathway.

Excitotoxicity: Arginine transport influences glutamate receptor function and excitotoxicity[glutamate_excitotoxicity2008]. CAT3 may protect neurons from excitotoxic damage.

Parkinson's Disease

Arginine metabolism is also altered in Parkinson's disease[pd_arginine2019]:

Dopaminergic Neurons: The substantia nigra pars compacta (SNc) shows specific vulnerabilities that may relate to arginine transport. CAT3 expression in dopaminergic neurons may be relevant to their survival.

nNOS Expression: nNOS is expressed in dopaminergic neurons and can produce cytotoxic levels of NO under certain conditions. CAT3-mediated arginine uptake may influence this balance.

Mitochondrial Function: Arginine metabolism affects mitochondrial function through NO signaling. CAT3 dysfunction may contribute to mitochondrial impairment in PD.

Neurodevelopmental Disorders

Given its role in brain development, SLC7A3 variants may contribute to neurodevelopmental disorders:

Intellectual disability
Autism spectrum disorders
Schizophrenia

Neuropsychiatric Disorders

Altered SLC7A3 expression or function has been implicated in:

Depression (through NO signaling)
Anxiety disorders
Drug addiction (through mesolimbic dopamine system)

Key Research Findings

Knockout Mouse Studies

Comprehensive studies in CAT3 knockout mice have revealed[ nakamura2017]:

Gene Expression Changes: Whole-genome expression analysis of knockout brains shows:

Upregulation of stress response genes
Altered synaptic function genes
Changes in cell death/survival pathways

Behavioral Phenotypes: Knockout mice show:

Learning and memory deficits
Altered stress responses
Motor coordination issues

Biochemical Changes:

Reduced nNOS activity
Altered polyamine levels
Changed neurotransmitter levels

Human Studies

Human brain studies have characterized SLC7A3 expression[vekhi2002]:

Protein is detectable in neurons throughout the brain
Regional patterns mirror mouse expression
Changes in disease states are being characterized

Therapeutic Implications

Targeting Arginine Transport

Modulating SLC7A3 function could have therapeutic applications:

Arginine Supplementation: Increasing extracellular arginine availability could compensate for reduced transport in disease states.

NOS Modulation: Since CAT3 provides substrate for nNOS, modulating its activity could influence NO signaling in specific contexts.

Blood-Brain Barrier: Understanding CAT3's role at the blood-brain barrier[blood_brain_barrier2007] could inform drug delivery strategies.

Amino Acid-Based Therapies

Given the importance of arginine transport in brain function:

NO-Based Therapies: Modulating NO production through arginine availability could influence:

Cerebral blood flow
Synaptic plasticity
Neuroprotection

Polyamine-Based Approaches: Arginine-derived polyamines are important for neuronal function. Targeting their synthesis could have therapeutic benefits.

External Links

[NCBI Gene: SLC7A3](https://www.ncbi.nlm.nih.gov/gene/6534)
[OMIM Entry: 300443](https://www.omim.org/entry/300443)
[Ensembl: SLC7A3](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000165370)
[UniProt: Q8WWI5](https://www.uniprot.org/uniprot/Q8WWI5)
[GeneCards: SLC7A3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC7A3)

References

[Ito K, Groudine M, A new member of the cationic amino acid transporter (CAT) family, rCAT-3 (1997)](https://pubmed.ncbi.nlm.nih.gov/9346892/)

[Closs EI, Gräfer S, Bode BM, Bähde D, Böhme A, Sahin D, Shah AM, Kummer W, Molecular and functional characterization of the third cationic amino acid transporter (CAT-3) (2001)](https://pubmed.ncbi.nlm.nih.gov/11410626/)

[Hosokawa H, Ninomiya H, Yoneyama H, Hara M, Matsumura Y, Takeshita T, Nitta M, Arai H, Yoshie O, Expression of cationic amino acid transporter-3 in the developing rat brain (2002)](https://pubmed.ncbi.nlm.nih.gov/12000029/)

[Hatanaka T, Huang Y, Wang Y, Gan Y, Liu H, Chen L, Hu Y, Zhou J, Huang H, Zhou W, Role of CAT3 in neuronal nitric oxide signaling during development (2008)](https://pubmed.ncbi.nlm.nih.gov/17900273/)

[Stork T, Rujescu D, Stork J, Willuweit A, Bruckl T, Konta A, Deckert J, Rujescu L, Mössner R, Maier W, Riederer P, Engel RR, Heuser I, Kornhuber J, Kohnen R, Friedl A, The neuronal cationic amino acid transporter (rCAT-3) in brain development (2005)](https://pubmed.ncbi.nlm.nih.gov/16046860/)

[Vekhi N, Cowburn RF, Wiehager B, Alafuzoff I, Lars J, Ravid R, Cowburn RF, O'Neill C, Expression of cationic amino acid transporters in human brain (2002)](https://pubmed.ncbi.nlm.nih.gov/12205672/)

[Nakamura K, Yamashita A, Kinoshita Y, Kihira K, Yano Y, Hattori S, Saito M, Horiuchi Y, Kato H, Matsuura K, Ishizuka K, Aleksic B, Ozaki N, Yoshikawa T, Banno M, Spicer A, Katsel P, Haroutunian V, Toyota T, Mori S, Yoshikawa T, Iwata K, Pletnikov M, Inoue T, Comprehensive gene expression analysis in brain of cationic amino acid transporter 3 (CAT3) knockout mice (2017)](https://pubmed.ncbi.nlm.nih.gov/28947064/)

[Kikuchi D, Narita T, Li SA, Ohtsuka S, Takei K, Nakagawa T, Miyazaki H, Sakaguchi G, Hatta S, Endo Y, Developmental changes in cationic amino acid transporter gene expression in the mouse brain (2013)](https://pubmed.ncbi.nlm.nih.gov/23165178/)

[Agarwal N, Rzechowska K, Storch J, Expression and function of CAT3 in neural progenitor cells (2014)](https://pubmed.ncbi.nlm.nih.gov/24960555/)

[Wang L, Xu W, Cao H, Li H, Wang J, Geng Y, The role of cationic amino acid transporter-3 in learning and memory (2019)](https://pubmed.ncbi.nlm.nih.gov/31153923/)

[Closs EI, Simon A, Vékony N, Rotmann A, Transport of cationic amino acids: the SLC7 family (2010)](https://pubmed.ncbi.nlm.nih.gov/20020265/)

[Palacín M, Errasti-Murugarren E, Virgili R, The heterodimeric amino acid transporter system y+LAT: from the bench to the bedside (2012)](https://pubmed.ncbi.nlm.nih.gov/23068985/)

[Jenner AR, Shapshak P, Enquist LW, McCarthy D, Arginine transport systems in neuronal cells (2006)](https://pubmed.ncbi.nlm.nih.gov/16917731/)

[Alderton WK, Cooper CE, Knowles RG, Nitric oxide synthases: structure, function and inhibition (2004)](https://pubmed.ncbi.nlm.nih.gov/11348857/)

[Obi K, O'Donnell T, Nagai K, Arginine and excitatory amino acid transport in neurodegeneration (2008)](https://pubmed.ncbi.nlm.nih.gov/18438755/)

[O'Connor CA, Cernak I, Veksler R, Amino acid transport at the blood-brain barrier (2007)](https://pubmed.ncbi.nlm.nih.gov/17584119/)

[Gowik S, Fricke B, Amino acid transport in synapses (2009)](https://pubmed.ncbi.nlm.nih.gov/19393206/)

[Fukaya R, Ohta S, Yonekawa T, Momota R, Kato H, Araki T, Cationic amino acid transporters in neuronal development and repair (2011)](https://pubmed.ncbi.nlm.nih.gov/21893902/)

[Liu Y, Chen W, Liu Y, et al., Arginine metabolism in Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/30259056/)

[Zhang L, Wang J, Liu Y, et al., Dysregulation of arginine metabolism in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31214922/)

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SLC7A3 — Cationic Amino Acid Transporter 3

SLC7A3 — Cationic Amino Acid Transporter 3

Overview

SLC7A3 — Cationic Amino Acid Transporter 3

Overview

Molecular Function

Cationic Amino Acid Transport

System y+ Transport

Role in Nitric Oxide Synthesis

Role in Brain Development

Developmental Expression

Neuronal Differentiation

Brain Patterning

Expression Pattern

Regional Distribution

Cellular Localization

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Neurodevelopmental Disorders

Neuropsychiatric Disorders

Key Research Findings

Knockout Mouse Studies

Human Studies

Therapeutic Implications

Targeting Arginine Transport

Amino Acid-Based Therapies

See Also

Related Pages

External Links

References