Franchi-Gazzola R, Dall'Asta V, Sala R, Visigalli R, Bevilacqua E, Gaccioli F, Gazzola G C, Bussolati O
Unit of General and Clinical Pathology, Department of Experimental Medicine, University of Parma, Parma, Italy.
Acta Physiol (Oxf). 2006 May-Jun;187(1-2):273-83. doi: 10.1111/j.1748-1716.2006.01552.x.
Sodium-dependent neutral amino acid transporter-2 (SNAT2), the ubiquitous member of SLC38 family, accounts for the activity of transport system A for neutral amino acids in most mammalian tissues. As the transport process performed by SNAT2 is highly energized, system A substrates, such as glutamine, glycine, proline and alanine, reach high transmembrane gradients and constitute major components of the intracellular amino acid pool. Moreover, through a complex array of exchange fluxes, involving other amino acid transporters, and of metabolic reactions, such as the synthesis of glutamate from glutamine, SNAT2 activity influences the cell content of most amino acids, thus determining the overall size and the composition of the intracellular amino acid pool. As amino acids represent a large fraction of cell organic osmolytes, changes of SNAT2 activity are followed by modifications in both cell amino acids and cell volume. This mechanism is utilized by many cell types to perform an effective regulatory volume increase (RVI) upon hypertonic exposure. Under these conditions, the expression of SNAT2 gene is induced and newly synthesized SNAT2 proteins are preferentially targeted to the cell membrane, leading to a significant increase of system A transport Vmax. In cultured human fibroblasts incubated under hypertonic conditions, the specific silencing of SNAT2 expression, obtained with anti-SNAT2 siRNAs, prevents the increase in system A transport activity, hinders the expansion of intracellular amino acid pool, and significantly delays cell volume recovery. These results demonstrate the pivotal role played by SNAT2 induction in the short-term hypertonic RVI and suggest that neutral amino acids behave as compatible osmolytes in hypertonically stressed cells.
钠依赖性中性氨基酸转运体2（SNAT2）是SLC38家族中普遍存在的成员，在大多数哺乳动物组织中负责中性氨基酸转运系统A的活性。由于SNAT2执行的转运过程高度耗能，系统A的底物，如谷氨酰胺、甘氨酸、脯氨酸和丙氨酸，能够达到较高的跨膜梯度，并构成细胞内氨基酸池的主要成分。此外，通过一系列复杂的交换通量（涉及其他氨基酸转运体）以及代谢反应（如由谷氨酰胺合成谷氨酸），SNAT2的活性影响大多数氨基酸的细胞含量，从而决定细胞内氨基酸池的总体大小和组成。由于氨基酸占细胞有机渗透溶质的很大一部分，SNAT2活性的变化会伴随着细胞氨基酸和细胞体积的改变。许多细胞类型利用这种机制在高渗暴露时进行有效的调节性容积增加（RVI）。在这些条件下，SNAT2基因的表达被诱导，新合成的SNAT2蛋白优先靶向细胞膜，导致系统A转运的Vmax显著增加。在高渗条件下培养的人成纤维细胞中，用抗SNAT2 siRNAs实现SNAT2表达的特异性沉默，可阻止系统A转运活性的增加，阻碍细胞内氨基酸池的扩张，并显著延迟细胞体积恢复。这些结果证明了SNAT2诱导在短期高渗RVI中所起的关键作用，并表明中性氨基酸在高渗应激细胞中作为相容性渗透溶质发挥作用。
