{{.infobox .infobox-gene}}
| Symbol | SLC7A3 |
| Full Name | Cationic Amino Acid Transporter 3 (CAT3) |
| Chromosome | Xq28 |
| NCBI Gene ID | 6534 |
| OMIM | 300443 |
| Ensembl ID | ENSG00000165370 |
| UniProt ID | Q8WWI5 |
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[1][2]. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
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:
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].
The SLC7 family includes multiple cationic amino acid transporters (CAT1-4), each with distinct expression patterns and functional properties[system_y_plus2012]:
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:
SLC7A3 is highly expressed during brain development, particularly in neuronal populations[hosokawa2002][3]:
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:
Adult Expression: In the adult brain, SLC7A3 is expressed in specific neuronal populations, particularly in the hippocampus, cortex, and cerebellum[4].
CAT3 plays a role in neuronal differentiation through several mechanisms[agarwal2014]:
Arginine Availability: Adequate intracellular arginine is required for:
Metabolic Programming: Arginine metabolism influences the metabolic state of developing neurons, affecting their survival and differentiation potential.
Studies in knockout mice have revealed important roles for SLC7A3 in brain development[stork2005]:
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).
Within neurons, CAT3 is localized to:
This subcellular distribution supports roles in synaptic function and dendritic arginine metabolism.
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.
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.
Given its role in brain development, SLC7A3 variants may contribute to neurodevelopmental disorders:
Altered SLC7A3 expression or function has been implicated in:
Comprehensive studies in CAT3 knockout mice have revealed[ nakamura2017]:
Gene Expression Changes: Whole-genome expression analysis of knockout brains shows:
Behavioral Phenotypes: Knockout mice show:
Biochemical Changes:
Human brain studies have characterized SLC7A3 expression[vekhi2002]:
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.
Given the importance of arginine transport in brain function:
NO-Based Therapies: Modulating NO production through arginine availability could influence:
Polyamine-Based Approaches: Arginine-derived polyamines are important for neuronal function. Targeting their synthesis could have therapeutic benefits.
Ito K, Groudine M. A new member of the cationic amino acid transporter (CAT) family, rCAT-3. J Biol Chem. 1997. ↩︎
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). J Physiol. 2001. ↩︎
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. Neuroscience. 2013. ↩︎
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. J Neurosci Res. 2002. ↩︎