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

Abstract

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.

Prolonged Hypoxia Augments L-Citrulline Transport By System A In The Newborn Piglet Pulmonary Circulation

“…25 SNATs are found in most mammalian cells. 11,12 Our finding that SNAT1 is expressed in multiple lung cell types, including airway epithelial cells, was therefore not surprising. Moreover, it is well known that a number of different transport systems may occur in the same cell membrane.…”

“…System A subtypes, which include SNAT1, SNAT2, and SNAT4 are characterized by a broader amino acid substrate profile than System N subtypes, which include SNAT3 and SNAT5. 12,23 More specifically, SNAT1 and SNAT2 (also referred to as ATA1 and ATA2 respectively) show a high affinity to alanine, serine, proline, and glycine but also recognize N-methylated amino acids, like 2-methylaminisobutyric acid. 12,24 SNAT3 (also referred to as SN1 or NAT) recognizes the classic System N substrates, 23 glutamine, asparagine, and histidine, whereas SNAT5 (also known as SN2) favours serine.…”

“…9 -11 SNATs are expressed in most cell types and are categorized as System A or System N, dependent in part on their functional properties. Recently, the SLC38 gene family of transporters were identified, renamed SNATs 1 -5, and subdivided based on the similarity of their transport properties to System A or System N. 12 Many factors, including hormones, growth factors, and hyperosmotic stress, have been associated with changes in the activities and expression of SNAT proteins. 9 -15 However, to date, little is known about the impact on SNAT expression or L-citrulline transport in PAECs from conditions such as hypoxia that are associated with the development of pulmonary hypertension.…”

Glutamate as a therapeutic target in psychiatric disorders

“…5,28,29 GLYT1 and SNAT transporters, both of which are sensitive to inhibition by sarcosine (N-methyl glycine) predominate in the forebrain, whereas GLYT2 transporters are co-localized with strychnine-sensitive inhibitory glycine receptors in the hindbrain. 30 As GLYT1 transporters are coupled to only two Na þ ions, as opposed to GLYT2 transporters, which are coupled to three, they maintain relatively, shallow intracellelular to extracellular gradients.…”

“…4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling.…”