Amino Acid Transport, Cell Volume and Regulation of Cell Growth

A cDNA clone encoding a plasma membrane alaninepreferring transporter (SAT2) has been isolated from glutamatergic neurons in culture and represents the second member of the system A family of neutral amino acid transporters. SAT2 displays a widespread distribution and is expressed in most tissues, including heart, adrenal gland, skeletal muscle, stomach, fat, brain, spinal cord, colon, and lung, with lower levels detected in spleen. No signal is detected in liver or testis. In the central nervous system, SAT2 is expressed in neurons. SAT2 is significantly up-regulated during differentiation of cerebellar granule cells and is absent from astrocytes in primary culture. The functional properties of SAT2, examined using transfected fibroblasts and in cRNA-injected voltage-clamped Xenopus oocytes, show that small aliphatic neutral amino acids are preferred substrates and that transport is voltage-and Na ؉ -dependent (1:1 stoichiometry), pH-sensitive, and inhibited by ␣-(methylamino)isobutyric acid (MeAIB), a specific inhibitor of system A. Kinetic analyses of alanine and MeAIB uptake by SAT2 are saturable, with Michaelis constants (K m ) of 200 -500 M. In addition to its ubiquitous role as a substrate for oxidative metabolism and a major vehicle of nitrogen transport, SAT2 may provide alanine to function as the amino group donor to ␣-ketoglutarate to provide an alternative source for neurotransmitter synthesis in glutamatergic neurons.

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“…K 0. 5 Ala was largely independent of V m , except at depolarized potentials (more positive than Ϫ10 mV), rising to 1 mM at ϩ30 mV.…”

Section: Resultsmentioning

confidence: 91%

A Novel System A Isoform Mediating Na+/Neutral Amino Acid Cotransport

Yao¹,

Mackenzie²,

Hong³

et al. 2000

Journal of Biological Chemistry

219

216

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“…1). In pursuing the present challenges to identify the physiological roles of the SLC38 family of proteins, investigators could do worse than to use as a starting point the wealth of information in the literature for classic System A and System N, including their hormonal regulation and relationships to volume regulation, nutrition, and metabolism [20,21,39,50,63,91]. Classic studies revealed System A as the major regulated Na + -dependent amino acid transport system, serving small, aliphatic amino acids.…”

Section: Functional Characteristics and Distribution Of The Slc38 Sysmentioning

confidence: 96%

Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family

Mackenzie

Erickson

2004

Pfl�gers Archiv European Journal of Physiology

457

365

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The sodium-coupled neutral amino acid transporters (SNAT) of the SLC38 gene family resemble the classically-described System A and System N transport activities in terms of their functional properties and patterns of regulation. Transport of small, aliphatic amino acids by System A subtypes (SNAT1, SNAT2, and SNAT4) is rheogenic and pH sensitive. The System N subtypes SNAT3 and SNAT5 also countertransport H(+), which may be key to their operation in reverse, and have narrower substrate profiles than do the System A subtypes. Glutamine emerges as a favored substrate throughout the family, except for SNAT4. The SLC38 transporters undoubtedly play many physiological roles including the transfer of glutamine from astrocyte to neuron in the CNS, ammonia detoxification and gluconeogenesis in the liver, and the renal response to acidosis. Probing their regulation has revealed additional roles, and recent work has considered SLC38 transporters as therapeutic targets in neoplasia.

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“…System A has been shown to be strongly expressed in transformed and malignant cells [5]. System A is upregulated during the cell cycle progression and cell growth in many cell types [8]. System A also appears to be primary target of proto-oncogene and oncogene action and may be a crucial regulator of cellular growth [5].…”

Section: Introductionmentioning

confidence: 99%

Uptake of [ N -methyl - 11 C]α-methylaminoisobutyric acid in untreated head and neck cancer studied by PET

Sutinen

Jyrkkiö

Alanen

et al. 2003

European Journal of Nuclear Medicine and Molecular Imaging

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Amino acid transport system A is expressed strongly in neoplastic cells. [ N-methyl-(11)C]alpha-Methylaminoisobutyric acid ((11)C-MeAIB) is a recently developed tracer for PET studies on system A amino acid transport. (11)C-MeAIB is a metabolically stable amino acid analogue which is transported from plasma into the tissue by system A. This study evaluated the kinetics of (11)C-MeAIB uptake from plasma into tumour tissue and normal tissues in 13 patients with untreated head and neck cancer. (11)C-MeAIB uptake in tumour was compared with histological grade and proliferative activity. Tracer uptake was quantitated by calculating the standardised uptake values (SUVs) and the kinetic influx constants ( K(i)) using graphical analysis. All tumours accumulated (11)C-MeAIB and were visualised clearly. In the graphical analysis, linear plots were achieved; the mean K(i) value of tumour was 0.056+/-0.026 min(-1), and the mean SUV was 6.1+/-2.7. A close correlation between graphically obtained K(i) and semi-quantitative SUV in tumours was found ( r=0.887, P=0.00005). We could not demonstrate a correlation between the uptake of (11)C-MeAIB and the grade of malignancy or the proliferative index, as assessed using Ki-67 immunohistochemical assay. Head and neck cancer can be effectively imaged with (11)C-MeAIB PET. (11)C-MeAIB showed active and rapid transport into tumour tissue and salivary glands. Further studies on the applicability of (11)C-MeAIB PET for radiation treatment planning in the head and neck region and the regulation of system A amino acid transport under different metabolic states are warranted.

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Amino Acid Transport, Cell Volume and Regulation of Cell Growth

Cited by 10 publications

References 151 publications

A Novel System A Isoform Mediating Na+/Neutral Amino Acid Cotransport

A Novel System A Isoform Mediating Na+/Neutral Amino Acid Cotransport

Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family

Uptake of [ N -methyl - 11 C]α-methylaminoisobutyric acid in untreated head and neck cancer studied by PET

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