SLC4A4 Membrane Protein Introduction

Introduction of SLC4A4

Solute carrier family 4 member 4 (SLC4A4) is an electrogenic sodium bicarbonate cotransporter 1 (NBCe1) that is involved in the regulation of bicarbonate secretion/absorption and intracellular pH. There are two identified electrogenic Na⁺-HCO3^- cotransporters in mammals: NBCe1 (SLC4A4) and NBCe2 (NBC4/SLC4A5). And a third NBCe is found in the invertebrate nervous system. These NBCe proteins cotransport Na⁺ and 2-3 HCO3^- across epithelial membranes or neuronal membranes.

Function of SLC4A4 Membrane Protein

SLC4A4 (NBCe1) functions as a sodium bicarbonate cotransporter that mediates the coupled movement of sodium and bicarbonate ions across the plasma membrane of many cells. This is an electrogenic process with Na⁺:HCO3^- stoichiometry varying from 1:2 to 1:3. Sodium bicarbonate cotransport is associated with bicarbonate influx/efflux at the basolateral membrane of cells and intracellular pH regulation. NBCe1 has been associated with pH regulation in enamel organ cells during enamel development in the mouse. Some NBCe1 variants may lead to the impairment of bicarbonate reabsorption in the renal proximal tubules, causing a decrease in the threshold of renal bicarbonate, resulting in proximal renal tubular acidosis. Besides, patients with the autosomal recessive manner proximal renal tubular acidosis may display the inactivative basolateral sodium bicarbonate cotransporter. And these patients also exert eye abnormalities, such as band keratopathy, glaucoma, and cataracts. In addition, other NBCe1 mutations have been related to familial hemiplegic migraine.

Fig.1 Topology of NBCe1. (Huynh, 2018)

Application of SLC4A4 Membrane Protein in Literature

1. Parks S.K and Pouyssegur J. The Na(+)/HCO3(-) co-transporter SLC4A4 plays a role in growth and migration of colon and breast cancer cells. Journal of Cellular Physiology. 2015, 230(8):1954-1963. PubMed ID: 25612232
   
   

   The experimental results suggest that SLC4A4 helps to the HCO3(-) transport and tumor cell phenotype, suggesting it can act as a potential target for tumor treatment.

2. Hanzu F.A., et al. Expression of TMEM16A and SLC4A4 in human pancreatic islets. Cellular Physiology & Biochemistry. 2011, 29(1-2):61-64. PubMed ID: 22415075
   
   

   The present findings support the view that both SLC4A4 and TMEM16A may be involved in the regulation of anion fluxes in insulin-producing cells in humans.

3. Jalali R., et al. NBCe1 (SLC4A4) a potential pH regulator in enamel organ cells during enamel development in the mouse. Cell & Tissue Research. 2014, 358(2):433-442. PubMed ID: 25012520
   
   

   The article indicates that the expression of NBCe1 in ameloblasts and the papillary layer cell depends on the developmental stage and possibly responds to pH changes.

4. Demirci F.Y., et al. Proximal renal tubular acidosis and ocular pathology: a novel missense mutation in the gene (SLC4A4) for sodium bicarbonate cotransporter protein (NBCe1). Molecular Vision. 2006, 12:324-330. PubMed ID: 16636648
   
   

   In the present study, authors identify a novel, homozygous, missense SLC4A4 mutation (Leu522Pro in kNBCe1) in patients with proximal renal tubular acidosis, short stature, and ocular pathology.

5. Inatomi J., et al. Mutational and functional analysis of SLC4A4 in a patient with proximal renal tubular acidosis. Pflügers Archiv. 2004, 448(4):438-444. PubMed ID: 15085340
   
   

   This article expands the range of kNBC1 mutations in permanent isolated proximal renal tubular acidosis with eye abnormalities and increases our understanding of the renal tubular mechanism that is essential for acid-base homeostasis.

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Reference

1. Huynh K W, et al. (2018). CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1. Nature Communications. 9(1): 900.

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