Nutritional Stress Induced by Amino Acid Starvation Results in Changes for Slc38 Transporters in Immortalized Hypothalamic Neuronal Cells and Primary Cortex Cells

Abstract

Amino acid sensing and signaling is vital for cells, and both gene expression and protein levels of amino acid transporters are regulated in response to amino acid availability. Here, the aim was to study the regulation of all members of the SLC38 amino acid transporter family, Slc38a1-11, in mouse brain cells following amino acid starvation. We reanalyzed microarray data for the immortalized hypothalamic cell line N25/2 subjected to complete amino acid starvation for 1, 2, 3, 5, or 16 h, focusing specifically on the SLC38 family. All 11 Slc38 genes were expressed in the cell line, and Slc38a1, Slc38a2, and Slc38a7 were significantly upregulated at 5 h and most strongly at 16 h. Here, protein level changes were measured for SLC38A7 and the orphan family member SLC38A11 which has not been studied under different amino acid starvation condition at protein level. At 5 h, no significant alteration on protein level for either SLC38A7 or SLC38A11 could be detected. In addition, primary embryonic cortex cells were deprived of nine amino acids, the most common amino acids transported by the SLC38 family members, for 3 h, 7 h or 12 h, and the gene expression was measured using qPCR. Slc38a1, Slc38a2, Slc38a5, Slc38a6, Slc38a9, and Slc38a10 were upregulated, while Slc38a3 and Slc38a7 were downregulated. Slc38a8 was upregulated at 5 h and downregulated at 12 h. In conclusion, several members from the SLC38 family are regulated depending on amino acid levels and are likely to be involved in amino acid sensing and signaling in brain.

Sodium hydrogen exchanger 9 NHE9 (SLC9A9) and its emerging roles in neuropsychiatric comorbidity

“…SLC9A9 is involved in iron transport and upregulated during chemo‐radiation therapy, starvation and iron‐deprivation (Beydoun et al, 2017; J. Chen, Wen, et al, 2015; J. Chen, Yang, et al, 2015; Fridley et al, 2016; Hellsten et al, 2017; Hellsten, Tripathi, Ceder, & Fredriksson, 2018; Ueda et al, 2017). In the context of malignancy, this is of life‐preserving importance, as cancers that upregulate SLC9A9 are more difficult to treat; but, this evidence also potentially explains the development of neuropsychiatric diseases, such as ADHD, and why there is evidence to suggest selective neuronal vulnerability (Hess, Akutagava‐Martins, Patak, Glatt, & Faraone, 2018; Hoogman et al, 2017).…”

Knockdown of SLC38 Transporter Ortholog – CG13743 Reveals a Metabolic Relevance in Drosophila

“…Based on phylogenetic analysis, CG13743 clusters closely to human SLC38 family and in close proximity with SLC38A11 (Supplementary Figure S1D). SLC38A11 still remains understudied and is an orphan member in SLC38 family in vertebrates (Hellsten et al, 2018). CG13743 clusters with human SLC38A11 as an outgroup to the entire SLC38A1-A6 cluster, suggesting it represents a pro-ortholog to the human SLC38A1-A6 and SLC38A11 branch.…”

“…The phylogenetic tree shows that CG13743 clusters closely with human SLC38 family and in close proximity to SLC38A11 (Supplementary Figure S1D). SLC38A11 is an orphan transporter from SLC38 family that has not been studied extensively and lack characterization and functional relevance in mouse model (Hellsten et al, 2018). Therefore, in this paper we have used Drosophila to show the functional relevance of CG13743.…”

“…Chan et al (2016) studied the importance of SLC38A3 and its capacity to transport glutamine and was shown to have a critical role in amino acid metabolism. Several other studies have pointed toward varied roles of SLC38 family members in metabolism, homeostasis, and neurotransmission (Bagchi et al, 2014;Hägglund et al, 2015;Hellsten et al, 2018).…”

The solute carrier SLC7A8 is a marker of favourable prognosis in ER-positive low proliferative invasive breast cancer

“…Amino acids, particularly glutamine and leucine, are essential for cancer cell growth, as they are critical for controlling protein translation and driving cell cycle progression through regulation of the mammalian target of rapamycin complex1 (mTORC1) pathway [1,2]. This pivotal need for intracellular amino acids is reflected in the increased expression of amino acid transport systems in the majority of cancers, which is regulated by various transcription factors such as c-MYC, hormone receptors, and nutrient starvation responses [3][4][5].…”