Cation‐Coupled Bicarbonate Transporters

Abstract

Cation-coupled HCO3− transport was initially identified in the mid-1970s when pioneering studies showed that acid extrusion from cells is stimulated by CO2/HCO3− and associated with Na+ and Cl− movement. The first Na+-coupled bicarbonate transporter (NCBT) was expression-cloned in the late 1990s. There are currently five mammalian NCBTs in the SLC4-family: the electrogenic Na,HCO3-cotransporters NBCe1 and NBCe2 (SLC4A4 and SLC4A5 gene products); the electroneutral Na,HCO3-cotransporter NBCn1 (SLC4A7 gene product); the Na+-driven Cl,HCO3-exchanger NDCBE (SLC4A8 gene product); and NBCn2/NCBE (SLC4A10 gene product), which has been characterized as an electroneutral Na,HCO3-cotransporter or a Na+-driven Cl,HCO3-exchanger. Despite the similarity in amino acid sequence and predicted structure among the NCBTs of the SLC4-family, they exhibit distinct differences in ion dependency, transport function, pharmacological properties, and interactions with other proteins. In epithelia, NCBTs are involved in transcellular movement of acid-base equivalents and intracellular pH control. In nonepithelial tissues, NCBTs contribute to intracellular pH regulation; and hence, they are crucial for diverse tissue functions including neuronal discharge, sensory neuron development, performance of the heart, and vascular tone regulation. The function and expression levels of the NCBTs are generally sensitive to intracellular and systemic pH. Animal models have revealed pathophysiological roles of the transporters in disease states including metabolic acidosis, hypertension, visual defects, and epileptic seizures. Studies are being conducted to understand the physiological consequences of genetic polymorphisms in the SLC4-members, which are associated with cancer, hypertension, and drug addiction. Here, we describe the current knowledge regarding the function, structure, and regulation of the mammalian cation-coupled HCO3− transporters of the SLC4-family.

Disrupting Na+,HCO3–-cotransporter NBCn1 (Slc4a7) delays murine breast cancer development

“…As shown in Figure 3a, breast organoids were dominated by cells positive for the epithelial cell marker cytokeratin (CK) 19 and showed low abundance of cells positive for the myofibroblast marker smooth muscle α-actin.…”

“…19 Genome-wide association studies indicate a possible link between the electroneutral Na + ,HCO 3 --cotransporter NBCn1 (SLC4A7) and breast cancer in women of multiple ethnicities. 20 This putative association is based on the single-nucleotide polymorphism rs4973768 in the 3' untranslated region of NBCn1 but has not been experimentally validated.…”

The Renal Sodium Bicarbonate Cotransporter NBCe2: Is It a Major Contributor to Sodium and pH Homeostasis?

“…The resultant carbonic acid is acted upon by CA IV to continue the process of bicarbonate reabsorption. The renal tubular reabsorption of bicarbonate helps to maintain normal plasma bicarbonate and pH [1, 2••, 3••, 4, 13, 18, 19]. Germline deletion of SLC4A4 (NBCe1) [33] or SLC4A5 (NBCe2) [34] in mice causes metabolic acidosis and hypertension in the case of SLC4A5 .…”

“…NBCe2 is located in these nephron segments [10•, 30]. The gene SLC4A5 , which encodes NBCe2 [2••, 3••, 9, 19], has been significantly associated with high blood pressure and/or salt sensitivity [42••, 43••, 44••, 45••, 46, 47]. The increased activity ofNBCe2 [44••, 45••, 46, 47] at the luminal membrane [43••], and decreased activity of NBCe1, at the basolateral membrane [48], in hypertension do not conflict with the increase in RPT sodium transport in the genetic hypertension [37–40].…”

Nitric oxide and pH modulation in gynaecological cancer

“…One of the roles of AE1 isoform in gastric cancer regards with induction of cancer progression and cancer cell proliferation , while AE1 knockdown suppresses tumour growth in vivo . Whether a reduced removal and increased take up of HCO 3 − via these mechanisms is responsible of the intracellular alkalization in epithelial ovarian cancer is unknown .…”