SLC5A1 Membrane Protein Introduction

Introduction of SLC5A1

SLC5A1 (solute carrier family 5 member 1), also known as SGLT1, NAGT, or D22S675, is an integral membrane protein with 664 amino acids length and has a molecular mass of about 73.5 kDa. In humans, it is encoded by the SLC5A1 gene located on the chromosome 22q12.3. SLC5A1 codes for a member that belongs to the family of sodium-dependent glucose transporters (SGLT). It is mainly expressed in the intestine and kidney, and also found in the trachea, brain, heart, testis, and prostate. The SLC5A1 protein, a glucose transporter, is regarded as a major player in transport across the brush-border membrane. And it acts as a primary mediator in transporting glucose and the structurally similar galactose across the cell membrane.

Function of SLC5A1 Membrane Protein

SLC5A1 is the first characterized of the large SLC5 family of Na⁺-dependent symporters and is involved in the active transport of glucose and galactose into eukaryotic and several prokaryotic cells, but with a poor affinity for galactose. It generally transports glucose and Na⁺ in a ratio of 1:2 and thereby generating adequate inward current to excite specific cells. SLC5A1 actively transports glucose from the lumen of the small intestine or the nephron against its concentration gradient by combining glucose uptake with that of Na⁺. In this transport model, the glucose is first accumulated within the epithelium by the SLC5A1 in the brush-border membrane and then moved out of the cell across the basolateral membrane by a facilitated transporter, GLUT2. Definitely, SLC5A1 is the primary intestinal transporter for glucose absorption, even at a high luminal glucose concentration. Moreover, it is also described to mediate glucose-induced incretin secretion. Mutations in this gene would result in a rare autosomal recessive disorder, congenital glucose-galactose malabsorption (cGGM).

Fig.1 Secondary structure model of human SGLT1. (Andrianesis, 2013)

Application of SLC5A1 Membrane Protein in Literature

1. Al-Suyufi Y., et al. SLC5A1 mutations in Saudi Arabian patients with congenital glucose-galactose malabsorption. J Pediatr Gastroenterol Nutr. 2018, 66(2): 250-252. PubMed ID: 28753187
   
   

   This article firstly shows data from 16 unrelated congenital glucose-galactose malabsorption (cGGM) diagnosed Saudi patients from consanguineous families with majority of them previously having positive family history of cGGM. Sequencing analysis of full SLC5A1 coding regions for all patients leads to the identification of four allelic variants in a homozygous state.

2. Du F., et al. Potent sodium/glucose cotransporter SGLT1/2 dual inhibition improves glycemic control without marked gastrointestinal adaptation or colonic microbiota changes in rodents. J Pharmacol Exp Ther. 2018, 365(3): 676-687. PubMed ID: 29674332
   
   

   The sodium/glucose cotransporters SGLT1/2 can transport glucose across the kidney tubule and intestinal brush border. The results show that potent dual SGLT1/2 inhibition lowers blood glucose by decreasing intestinal glucose absorption and renal glucose threshold but minimally affects the luminal microbiota or intestinal mucosa in chow-fed rodents.

3. Salker M.S., et al. Loss of endometrial sodium glucose cotransporter SGLT1 is detrimental to embryo survival and fetal growth in pregnancy. Sci Rep. 2017, 7(1): 12612. PubMed ID: 28974690
   
   

   The expression of SLC5A1 in humans is upregulated upon decidualization of primary endometrial stromal cells. Compared with control subjects, endometrial SLC5A1 level during the implantation window is reduced in patients with recurrent pregnancy loss. The findings reveal a novel mechanism building abundant endometrial glycogen stores for pregnancy.

4. Steinhauser C.B., et al. Identification of appropriate reference genes for qPCR analyses of placental expression of SLC7A3 and induction of SLC5A1 in porcine endometrium. Placenta. 2017, 52: 1-9. PubMed ID: 28454689
   
   

   SLC5A1 is induced in uterine luminal epithelium (LE) by estrogen of trophectoderm origin when the blastocyst is free-floating and relies on glucose from the endometrium, while SLC7A3 is expressed in established placenta to support the fetal growth.

5. Lehmann A. and Hornby P.J. Intestinal SGLT1 in metabolic health and disease. Am J Physiol Gastrointest Liver Physiol. 2016, 310(11): G887-898. PubMed ID: 27012770
   
   

   Recent results from patients treated with dual SGLT1/2 inhibitors or SGLT2-selective drugs (such as canagliflozin) warrant the evaluation of SGLT1 inhibition for type 2 diabetes mellitus (T2DM). Compounds that restrain SGLT1 must balance the modulation of the mechanisms to achieve therapeutic efficacy for metabolic diseases.

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Reference

1. Andrianesis V and Doupis J. (2013). The role of kidney in glucose homeostasis--SGLT2 inhibitors, a new approach in diabetes treatment. Expert Rev Clin Pharmacol. 6(5), 519-539.

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