Mis-trafficking of bicarbonate transporters: implications to human diseasesThis paper is one of a selection of papers published in a Special Issue entitled CSBMCB 53rd Annual Meeting — Membrane Proteins in Health and Disease, and has undergone the Journal’s usual peer review process (original) (raw)
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The mitochondrial transporter family (SLC25): physiological and pathological implications
Pfl�gers Archiv European Journal of Physiology, 2004
The mitochondrial carriers (MCs) shuttle a variety of metabolites across the inner mitochondrial membrane (i.m.m.). In man they are encoded by the SLC25 genes. Some MCs have isoforms encoded by different SLC25 genes, whereas the phosphate carrier has two variants arising from an alternative splicing of SLC25A3. Six MCs have been sequenced after purification, and many more have been identified from their transport and kinetic properties following heterologous over-expression and reconstitution into liposomes. All MCs of known function belong to the same protein family, since their polypeptide chains consist of three tandemly related sequences of about 100 amino acids, and the repeats of the different carriers are homologous. They probably function as homodimers, each monomer being folded in the membrane into six transmembrane segments. The functional information obtained in studies with mitochondria and/or the reconstituted system has helped to gain an insight into the physiological role of the MCs in cell metabolism, as have tissue distribution, the use of knock-out mice (and/or yeast) and over-expression in human cell lines (or yeast) of individual carriers and isoforms. At the same time, the cloning and functional identification of many SLC25 genes has made it possible (i) to identify the genes (and their defects) responsible for some diseases, e.g. Stanley syndrome and Amish microcephaly, and (ii) where the genes were already known, to characterize the function of the gene products and hence understand the molecular basis and the symptoms of the diseases, e.g. hyperornithinaemia, hyperammonaemia and homocitrullinuria (HHH) syndrome and type II citrullinemia. It is likely that further extension and functional characterization of the SLC25 gene family will elucidate other diseases caused by MC deficiency.
The SLC4 family of bicarbonate transporters
Molecular Aspects of Medicine, 2013
The SLC4 family consists of ten genes (SLC4A1-5; SLC4A7-11). All encode integral membrane proteins with very similar hydropathy plots-consistent with 10-14 transmembrane segments. Nine SLC4 members encode proteins that transport (or a related species, such as) across the plasma membrane. Functionally, eight of these proteins fall into two major groups: three Cl-HCO 3 exchangers (AE1-3) and five Na +-coupled transporters (NBCe1, NBCe2, NBCn1, NBCn2, NDCBE). Two of the Na +-coupled transporters (NBCe1, NBCe2) are electrogenic; the other three Na +-coupled transporters and all three AEs are electroneutral. In addition, two other SLC4 members (AE4, SLC4A9 and BTR1, SLC4A11) do not yet have a firmly established function. Most, though not all, SLC4 members are functionally inhibited by 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS). SLC4 proteins play important roles many modes of acid-base homeostasis: the carriage of CO 2 by erythrocytes, the transport of H + or by several epithelia, as well as the regulation of cell volume and intracellular pH.
Regulators of Slc4 bicarbonate transporter activity
The Slc4 family of transporters is comprised of anion exchangers (AE1-4), Na(+)-coupled bicarbonate transporters (NCBTs) including electrogenic Na/bicarbonate cotransporters (NBCe1 and NBCe2), electroneutral Na/bicarbonate cotransporters (NBCn1 and NBCn2), and the electroneutral Na-driven Cl-bicarbonate exchanger (NDCBE), as well as a borate transporter (BTR1). These transporters regulate intracellular pH (pHi) and contribute to steady-state pHi, but are also involved in other physiological processes including CO2 carriage by red blood cells and solute secretion/reabsorption across epithelia. Acid-base transporters function as either acid extruders or acid loaders, with the Slc4 proteins moving HCO(-) 3 either into or out of cells. According to results from both molecular and functional studies, multiple Slc4 proteins and/or associated splice variants with similar expected effects on pHi are often found in the same tissue or cell. Such apparent redundancy is likely to be physiologically important. In addition to regulating pHi, a HCO(-) 3 transporter contributes to a cell's ability to fine tune the intracellular regulation of the cotransported/exchanged ion(s) (e.g., Na(+) or Cl(-)). In addition, functionally similar transporters or splice variants with different regulatory profiles will optimize pH physiology and solute transport under various conditions or within subcellular domains. Such optimization will depend on activated signaling pathways and transporter expression profiles. In this review, we will summarize and discuss both well-known and more recently identified regulators of the Slc4 proteins. Some of these regulators include traditional second messengers, lipids, binding proteins, autoregulatory domains, and less conventional regulators. The material presented will provide insight into the diversity and physiological significance of multiple members within the Slc4 gene family.
A novel sodium bicarbonate cotransporter-like gene in an ancient duplicated region: SLC4A9 at 5q31
Genome Biology - GENOME BIOL, 2001
BACKGROUND: Sodium bicarbonate cotransporter (NBC) genes encode proteins that execute coupled Na+ and HCO3- transport across epithelial cell membranes. We report the discovery, characterization, and genomic context of a novel human NBC-like gene, SLC4A9, on chromosome 5q31. RESULTS: SLC4A9 was initially discovered by genomic sequence annotation and further characterized by sequencing of long-insert cDNA library clones. The predicted protein of 990 amino acids has 12 transmembrane domains and high sequence similarity to other NBCs. The 23-exon gene has 14 known mRNA isoforms. In three regions, mRNA sequence variation is generated by the inclusion or exclusion of portions of an exon. Noncoding SLC4A9 cDNAs were recovered multiple times from different libraries. The 3' untranslated region is fragmented into six alternatively spliced exons and contains expressed Alu, LINE and MER repeats. SLC4A9 has two alternative stop codons and six polyadenylation sites. Its expression is largel...
Journal of Biological Chemistry, 2002
The organic anion transporter SLC21A6 (also known as OATP2, OATP-C, or LST-1) is involved in the hepatocellular uptake of a variety of endogenous and xenobiotic substances and drugs. We analyzed 81 human liver samples by immunoblotting and found one with a strongly reduced amount of SLC21A6 protein suggesting mutations in the SLC21A6 gene. The SLC21A6 cDNA from this sample contained five base pair changes in one allele; three of the mutations resulted in amino acid substitutions designated SLC21A6-N130D, SLC21A6-P155T, and SLC21A6-L193R. The former two were polymorphisms (SLC21A6*1b and SLC21A6*4), whereas SLC21A6-L193R represents the first naturally occurring mutation identified in one allele of the SLC21A6 gene, which affects protein maturation and organic anion transport. We introduced each of the mutations into the SLC21A6 cDNA and established stably transfected MD-CKII cells expressing the respective mutant SLC21A6 protein. Immunofluorescence microscopy and uptake measurements were used to study localization and transport properties of the mutated proteins. Both proteins carrying the polymorphisms were sorted to the lateral membrane like wild-type SLC21A6, but their transport properties for the substrates cholyltaurine and 17-glucuronosyl estradiol were altered. Importantly, most of the mutant protein SLC21A6-L193R was retained intracellularly, and this single amino acid exchange abolished transport function.
Estrogenic regulation of bicarbonate transporters from SLC4 family in rat Sertoli cells
Molecular and cellular biochemistry, 2015
The formation of competent spermatozoa is a complex event that depends on the establishment of adequate environments throughout the male reproductive tract. Bicarbonate is essential not only to ionic homeostasis but also to pH maintenance along the male reproductive tract. Previous studies support an association of high 17β-estradiol (E2) levels with modulation of specific ion transporters expression. Herein we determined the effect of E2 on the expression/functionality of SLC4 family bicarbonate transporters in rat Sertoli cells (SCs). All studied transporters [anion exchanger 2 (AE2), Na(+)-driven Cl(-)/HCO3 (-) exchanger (NDCBE), electrogenic Na(+)/HCO3 (-) co-transporters (NBCe1), and electroneutral Na(+)/HCO3 (-) co-transporters (NBCn1)] were identified in SCs, being AE2 and NBCn1 the most abundant. In E2-treated cells (100 nM), increases in AE2 and NBCn1 protein levels were observed, as well as altered transcellular transport. E2-treated SCs presented a significant perturbatio...
The Physiopathological Role of the Exchangers Belonging to the SLC37 Family
Frontiers in Chemistry
The human SLC37 gene family includes four proteins SLC37A1-4, localized in the endoplasmic reticulum (ER) membrane. They have been grouped into the SLC37 family due to their sequence homology to the bacterial organophosphate/phosphate (Pi) antiporter. SLC37A1-3 are the less characterized isoforms. SLC37A1 and SLC37A2 are Pi-linked glucose-6-phosphate (G6P) antiporters, catalyzing both homologous (Pi/Pi) and heterologous (G6P/Pi) exchanges, whereas SLC37A3 transport properties remain to be clarified. Furthermore, SLC37A1 is highly homologous to the bacterial glycerol 3-phosphate permeases, so it is supposed to transport also glycerol-3-phosphate. The physiological role of SLC37A1-3 is yet to be further investigated. SLC37A1 seems to be required for lipid biosynthesis in cancer cell lines, SLC37A2 has been proposed as a vitamin D and a phospho-progesterone receptor target gene, while mutations in the SLC37A3 gene appear to be associated with congenital hyperinsulinism of infancy. SLC37A4, also known as glucose-6-phosphate translocase (G6PT), transports G6P from the cytoplasm into the ER lumen, working in complex with either glucose-6-phosphatase-α (G6Pase-α) or G6Pase-β to hydrolyze intraluminal G6P to Pi and glucose. G6PT and G6Pase-β are ubiquitously expressed, whereas G6Pase-α is specifically expressed in the liver, kidney and intestine. G6PT/G6Pase-α complex activity regulates fasting blood glucose levels, whereas G6PT/G6Pase-β is required for neutrophil functions. G6PT deficiency is responsible for glycogen storage disease type Ib (GSD-Ib), an autosomal recessive disorder associated with both defective metabolic and myeloid phenotypes. Several kinds of mutations have been identified in the SLC37A4 gene, affecting G6PT function. An increased autoimmunity risk for GSD-Ib patients has also been reported, moreover, SLC37A4 seems to be involved in autophagy.
Genomics, 1997
adenylation signals, and promoter of the human Na / / bers of the family, the electrochemical gradient for Na / myo-inositol cotransporter (SLC5A3) gene have been provides the driving force for active MI transport. In elucidated through cloning, sequencing, mRNA analyaddition, the SLC5A3 gene plays an important role in ses, and reporter gene assays. The gene consists of one mammalian osmoregulation, allowing cells to maintain promoter and two exons spanning approximately 26 cell volume regulation but not at the expense of perkb. Exon 1 contains 175 bp of 5 untranslated sequence turbing cellular ion concentrations (Thurston et al., and is 15 kb upstream of exon 2. The 9.5-kb exon 2 1989; Strange et al., 1991, 1994; Handler and Kwon, contains the entire 2157-bp open reading frame and 1996). a large 3 untranslated sequence with seven putative We recently cloned the human SLC5A3 gene and sepolyadenylation signals. Multiple messages with difquenced the coding region (Berry et al., 1995). Like the ferent-sized 3 untranslated regions can be detected on canine and bovine SLC5A3 genes (Rim et al., 1997; Northern blots. Hypertonic stress caused mRNA levels, Berry et al., 1995; Mallee et al., 1995), it is atypical and primarily that of the full-length 9.5-kb transcript, in that the coding region is intron-free and contained to increase in cultured melanoma cells; ribonuclease within an exceptionally large exon. The human gene protection analysis demonstrated that the transcriphas been fine-mapped to chromosome 21q22.1 (Berry tion start site was the same in stressed as in control et al., 1996). It is expressed in many tissues including cells. The SLC5A3 gene functions in cellular osmoregubrain, kidney, and placenta (Berry et al., 1995). The lation and is expressed in many human tissues includmajority of patients with trisomy 21 (Epstein, 1995) ing the brain, kidney, and placenta. It is localized to may be unable to repress the expression of the three chromosome 21q22.1. An overexpression of the SLC5A3 gene deserves consideration as a factor in the patho-SLC5A3 genes so that both energy-dependent uptake physiology of Down syndrome. ᭧ 1997 Academic Press and facilitated efflux of MI could be increased in some or all cells that express SLC5A3 genes (Fruen and Lester, 1990, 1991). To identify potential genetic factors MATERIALS AND METHODS the precursor of the signal-transducing phosphoinosi-Isolation of genomic clones. The first human SLC5A3 genomic clone that was isolated was from a bacteriophage lambda FIX II Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under Accession No. AF027153. library from Stratagene Cloning Systems (La Jolla, CA) (Berry et al., 1995). Primers corresponding to a portion of the 3 untranslated J. J. Mallee and M. G. Atta contributed equally to this work. 1 To whom correspondence should be addressed at Division of Bio-region were used to screen a human bacteriophage P1 library from Genome Systems, Inc. (St. Louis, MO) using PCR (Berry et al., 1995). chemical Development and Molecular Diseases, The Children's Hospital of Philadelphia, 34th Street & Civic Center Boulevard, Philadel-Two overlapping clones (P1 3283 and P1 3284) were isolated from this library with average inserts of 90 kb. The P1 clones were di-phia, Pennsylvania 19104. Telephone: (215) 590-3372. Fax: (215) 590-3364. gested as described below, and fragments were subcloned in pBlue-459
The SLC13 gene family of sodium sulphate/carboxylate cotransporters
Pfl�gers Archiv European Journal of Physiology, 2004
The SLC13 gene family consist of five sequence-related members that have been identified in a variety of animals, plants, yeast and bacteria. Proteins encoded by these genes are divided into two functionally unrelated groups: the Na + -sulphate (NaS) cotransporters and the Na + -carboxylate (NaC) cotransporters. Members of this family include the renal Na + -dependent inorganic sulphate transporter-1 (NaSi-1, SLC13A1), the Na +dependent dicarboxylate transporters NaDC-1/SDCT1 (SLC13A2), NaDC-3/SDCT2 (SLC13A3), the sulphate transporter-1 (SUT-1, SLC13A4) and the Na + -coupled citrate transporter (NaCT, SLC13A5). The general characteristics of the SLC13 proteins are that they encode multi-spanning proteins with 8-13 transmembrane domains, have a wide tissue distribution with most being expressed in the epithelial cells of the kidney and the gastrointestinal tract. They are Na + -coupled symporters, DIDS-insensitive, with strong cation preference for Na + , with a Na + :anion coupling ratio of around 3:1 and have a substrate preference for divalent anions, which include tetraoxyanions (for the NaS cotransporters) or Krebs cycle intermediates, including mono-, di-, and tri-carboxylates (for the NaC cotransporters). The purpose of this review is to provide an update on the most recent advances and to summarize the biochemical, physiological and structural aspects of the vertebrate SLC13 gene family.