Pendrin

Last updated
SLC26A4
Identifiers
Aliases SLC26A4 , DFNB4, EVA, PDS, TDH2B, solute carrier family 26 member 4
External IDs OMIM: 605646; MGI: 1346029; HomoloGene: 20132; GeneCards: SLC26A4; OMA:SLC26A4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5172

23985

Ensembl

ENSG00000091137

ENSMUSG00000020651

UniProt

O43511

Q9R155

RefSeq (mRNA)

NM_000441

NM_011867

RefSeq (protein)

NP_000432

NP_035997

Location (UCSC) Chr 7: 107.66 – 107.72 Mb Chr 12: 31.57 – 31.61 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Pendrin is an anion exchange protein that in humans is encoded by the SLC26A4 gene (solute carrier family 26, member 4). [5] [6] Pendrin was initially identified as a sodium-independent chloride-iodide exchanger [7] with subsequent studies showing that it also accepts formate and bicarbonate as substrates. [8] [9] Pendrin is similar to the Band 3 transport protein found in red blood cells. Pendrin is the protein which is mutated in Pendred syndrome, which is an autosomal recessive disorder characterized by sensorineural hearing loss, goiter and a partial organification problem detectable by a positive perchlorate test. [10]

Contents

Pendrin is responsible for mediating the electroneutral exchange of chloride (Cl−) for bicarbonate (HCO3−) across a plasma membrane in the chloride cells of freshwater fish.

By phylogenetic analysis, pendrin has been found to be a close relative of prestin present on the hair cells or organ of corti in the inner ear. Prestin is primarily an electromechanical transducer but pendrin is an ion transporter.

Function

Pendrin is an ion exchanger found in many types of cells in the body. High levels of pendrin expression have been identified in the inner ear and thyroid. [11]

Thyroid

Thyroid hormone synthesis, with Pendrin seen at center between the follicular colloid and the follicular cell. Thyroid hormone synthesis.svg
Thyroid hormone synthesis, with Pendrin seen at center between the follicular colloid and the follicular cell.

In the thyroid, pendrin is expressed by thyroid follicular cells. Na+/I− symporter imports iodide (I-) into the cell across its basolateral side, and pendrin extrudes the I− across the cell's apical membrane into the thyroid colloid. [12]

Inner ear

The exact function of pendrin in the inner ear remains unclear; however, pendrin may play a role in acid-base balance as a chloride-bicarbonate exchanger, regulate volume homeostasis through its ability to function as a chloride-formate exchanger [13] [14] or indirectly modulate the calcium concentration of the endolymph. [15] Pendrin is also expressed in the kidney, and has been localized to the apical membrane of a population of intercalated cells in the cortical collecting duct where it is involved in bicarbonate secretion. [16] [17]

Kidney

Renal β-intercalated cells of the late distal tube and collecting duct express pendrin upon their apical membrane, resorbing one Cl− in exchange for secreting a HCO3−, with Cl− subsequently extruded from the cell by a basolateral Cl− channel. β-intercalated cells thus utilise pendrin to contribute to acid-base homeostasis by excreting base (HCO3−) into urine. Additionally, β-intercalated cells may use pendrin in concert with a Na+/HCO3−/2Cl− antiporter in order to resorb NaCl. [18]

Clinical significance

Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. Pendred syndrome is characterized by thyroid goiter and enlargement of the vestibular aqueduct resulting in deafness; however, despite being expressed in the kidney, individuals with Pendred syndrome do not show any kidney-related acid-base, or volume abnormalities under basal conditions. This is probably the result of other bicarbonate or chloride transporters in the kidney compensating for any loss of pendrin function. Only under extreme situations of salt depletion or metabolic alkalosis, or with inactivation of the sodium-chloride cotransporter, are fluid and electrolyte disorders manifested in these patients. [19] SLC26A4 is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [5]

Another little-understood role of pendrin is in airway hyperreactivity and inflammation, as during asthma attacks and allergic reactions. Expression of pendrin in the lung increases in response to allergens and high concentrations of IL-13, [20] [21] and overexpression of pendrin results in airway inflammation, hyperreactivity, and increased mucus production. [22] [23] These symptoms could result from pendrin's effects on ion concentration in the airway surface liquid, possibly causing the liquid to be less hydrated. [24]

Related Research Articles

<span class="mw-page-title-main">Antiporter</span> Class of transmembrane transporter protein

An antiporter is an integral membrane protein involved in secondary active transport. It is a type of cotransporter, which means that uses the movement of one In the case of an antiporter, two or more different molecules or ions are moved across a phospholipid membrane, such as the plasma membrane, in opposite directions, one into the cell and one out of the cell. This is in contrast to symporters, which are another type of cotransporter that moves two or more ions in the same direction.

<span class="mw-page-title-main">Cotransporter</span> Type of membrane transport proteins

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable coupled or cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

<span class="mw-page-title-main">Cystic fibrosis transmembrane conductance regulator</span> Mammalian protein found in humans

Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene.

<span class="mw-page-title-main">Pendred syndrome</span> Medical condition

Pendred syndrome is a genetic disorder leading to congenital bilateral sensorineural hearing loss and goitre with euthyroid or mild hypothyroidism. There is no specific treatment, other than supportive measures for the hearing loss and thyroid hormone supplementation in case of hypothyroidism. It is named after Vaughan Pendred (1869–1946), the British doctor who first described the condition in an Irish family living in Durham in 1896. It accounts for 7.5% to 15% of all cases of congenital deafness.

<span class="mw-page-title-main">Chloride channel</span> Class of transport proteins

Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels have been characterized in humans.

<span class="mw-page-title-main">Prestin</span> Protein-coding gene in the species Homo sapiens

Prestin is a protein that is critical to sensitive hearing in mammals. It is encoded by the SLC26A5 gene.

<span class="mw-page-title-main">Band 3 anion transport protein</span> Mammalian protein found in Homo sapiens

Band 3 anion transport protein, also known as anion exchanger 1 (AE1) or band 3 or solute carrier family 4 member 1 (SLC4A1), is a protein that is encoded by the SLC4A1 gene in humans.

<span class="mw-page-title-main">Sulfate transporter</span> Protein-coding gene in the species Homo sapiens

The sulfate transporter is a solute carrier family protein that in humans is encoded by the SLC26A2 gene. SLC26A2 is also called the diastrophic dysplasia sulfate transporter (DTDST), and was first described by Hästbacka et al. in 1994. A defect in sulfate activation described by Superti-Furga in achondrogenesis type 1B was subsequently also found to be caused by genetic variants in the sulfate transporter gene. This sulfate (SO42−) transporter also accepts chloride, hydroxyl ions (OH−), and oxalate as substrates. SLC26A2 is expressed at high levels in developing and mature cartilage, as well as being expressed in lung, placenta, colon, kidney, pancreas and testis.

<span class="mw-page-title-main">Carbonic anhydrase II</span> Enzyme found in humans

Carbonic anhydrase II is one of sixteen forms of human α carbonic anhydrases. Carbonic anhydrase catalyzes reversible hydration of carbon dioxide. Defects in this enzyme are associated with osteopetrosis and renal tubular acidosis. Renal carbonic anhydrase allows the reabsorption of bicarbonate ions in the proximal tubule. Loss of carbonic anhydrase activity in bones impairs the ability of osteoclasts to promote bone resorption, leading to osteopetrosis.

<span class="mw-page-title-main">CLCN5</span> Mammalian protein found in humans

The CLCN5 gene encodes the chloride channel Cl-/H+ exchanger ClC-5. ClC-5 is mainly expressed in the kidney, in particular in proximal tubules where it participates to the uptake of albumin and low-molecular-weight proteins, which is one of the principal physiological role of proximal tubular cells. Mutations in the CLCN5 gene cause an X-linked recessive nephropathy named Dent disease characterized by excessive urinary loss of low-molecular-weight proteins and of calcium (hypercalciuria), nephrocalcinosis and nephrolithiasis.

<span class="mw-page-title-main">Sodium bicarbonate cotransporter 3</span> Protein-coding gene in the species Homo sapiens

Sodium bicarbonate cotransporter 3 is a protein which in humans is encoded by the SLC4A7 gene.

<span class="mw-page-title-main">Multidrug resistance-associated protein 2</span> Protein found in humans

Multidrug resistance-associated protein 2 (MRP2) also called canalicular multispecific organic anion transporter 1 (cMOAT) or ATP-binding cassette sub-family C member 2 (ABCC2) is a protein that in humans is encoded by the ABCC2 gene.

<span class="mw-page-title-main">Electrogenic sodium bicarbonate cotransporter 1</span> Protein-coding gene in the species Homo sapiens

Electrogenic sodium bicarbonate cotransporter 1, sodium bicarbonate cotransporter is a membrane transport protein that in humans is encoded by the SLC4A4 gene.

<span class="mw-page-title-main">Anion exchange protein 2</span> Protein-coding gene in the species Homo sapiens

Anion exchange protein 2 (AE2) is a membrane transport protein that in humans is encoded by the SLC4A2 gene. AE2 is functionally similar to the Band 3 Cl−/HCO3− exchange protein.

<span class="mw-page-title-main">Chloride anion exchanger</span> Protein-coding gene in the species Homo sapiens

Chloride anion exchanger, also known as down-regulated in adenoma, is a protein that in humans is encoded by the SLC26A3 gene.

<span class="mw-page-title-main">Anion exchange protein 3</span> Protein-coding gene in the species Homo sapiens

Anion exchange protein 3 is a membrane transport protein that in humans is encoded by the SLC4A3 gene. AE3 is functionally similar to the Band 3 Cl−/HCO3− exchange protein but it is expressed primarily in brain neurons and in the heart. Like AE2 its activity is sensitive to pH. AE3 mutations have been linked to seizures.

<span class="mw-page-title-main">SLC26A6</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 26 member 6 is a protein that in humans is encoded by the SLC26A6 gene. It is an anion-exchanger expressed in the apical membrane of the kidney proximal tubule, the apical membranes of the duct cells in the pancreas, and the villi of the duodenum.

<span class="mw-page-title-main">Anion exchange transporter</span> Protein-coding gene in the species Homo sapiens

Anion exchange transporter is a protein that in humans is encoded by the SLC26A7 gene.

<span class="mw-page-title-main">Congenital chloride diarrhea</span> Medical condition

Congenital chloride diarrhea is a genetic disorder due to an autosomal recessive mutation on chromosome 7. The mutation is in downregulated-in-adenoma (DRA), a gene that encodes a membrane protein of intestinal cells. The protein belongs to the solute carrier 26 family of membrane transport proteins. More than 20 mutations in the gene are known to date. A rare disease, CCD occurs in all parts of the world but is more common in some populations with genetic founder effects, most notably in Finland.

The anion exchanger family is a member of the large APC superfamily of secondary carriers. Members of the AE family are generally responsible for the transport of anions across cellular barriers, although their functions may vary. All of them exchange bicarbonate. Characterized protein members of the AE family are found in plants, animals, insects and yeast. Uncharacterized AE homologues may be present in bacteria. Animal AE proteins consist of homodimeric complexes of integral membrane proteins that vary in size from about 900 amino acyl residues to about 1250 residues. Their N-terminal hydrophilic domains may interact with cytoskeletal proteins and therefore play a cell structural role. Some of the currently characterized members of the AE family can be found in the Transporter Classification Database.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000091137 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000020651 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: SLC26A4 solute carrier family 26, member 4".
  6. ↑ Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, et al. (December 1997). "Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS)". Nature Genetics. 17 (4): 411–422. doi:10.1038/ng1297-411. PMID   9398842. S2CID   39359838.
  7. ↑ Scott DA, Wang R, Kreman TM, Sheffield VC, Karniski LP (April 1999). "The Pendred syndrome gene encodes a chloride-iodide transport protein". Nature Genetics. 21 (4): 440–443. doi:10.1038/7783. PMID   10192399. S2CID   23717390.
  8. ↑ Scott DA, Karniski LP (January 2000). "Human pendrin expressed in Xenopus laevis oocytes mediates chloride/formate exchange". American Journal of Physiology. Cell Physiology. 278 (1): C207–C211. doi: 10.1152/ajpcell.2000.278.1.c207 . PMID   10644529. S2CID   18841371.
  9. ↑ Soleimani M, Greeley T, Petrovic S, Wang Z, Amlal H, Kopp P, et al. (February 2001). "Pendrin: an apical Cl-/OH-/HCO3- exchanger in the kidney cortex". American Journal of Physiology. Renal Physiology. 280 (2): F356–F364. doi:10.1152/ajprenal.2001.280.2.f356. PMID   11208611.
  10. ↑ Patterson C, Runge MS (2006). Principles of molecular medicine. Totowa, NJ: Humana Press. p. 957. ISBN   1-58829-202-9.
  11. ↑ Bizhanova A, Kopp P (2011-01-01). "Controversies concerning the role of pendrin as an apical iodide transporter in thyroid follicular cells". Cellular Physiology and Biochemistry. 28 (3): 485–490. doi: 10.1159/000335103 . PMID   22116361.
  12. ↑ Kessler J, Obinger C, Eales G (July 2008). "Factors influencing the study of peroxidase-generated iodine species and implications for thyroglobulin synthesis". Thyroid. 18 (7): 769–774. doi:10.1089/thy.2007.0310. PMID   18631006.
  13. ↑ Karniski LP, Aronson PS (September 1985). "Chloride/formate exchange with formic acid recycling: a mechanism of active chloride transport across epithelial membranes". Proceedings of the National Academy of Sciences of the United States of America. 82 (18): 6362–6365. Bibcode:1985PNAS...82.6362K. doi: 10.1073/pnas.82.18.6362 . PMC   391054 . PMID   3862136.
  14. ↑ Kim HM, Wangemann P (November 2010). "Failure of fluid absorption in the endolymphatic sac initiates cochlear enlargement that leads to deafness in mice lacking pendrin expression". PLOS ONE. 5 (11): e14041. Bibcode:2010PLoSO...514041K. doi: 10.1371/journal.pone.0014041 . PMC   2984494 . PMID   21103348.
  15. ↑ Wangemann P, Nakaya K, Wu T, Maganti RJ, Itza EM, Sanneman JD, et al. (May 2007). "Loss of cochlear HCO3- secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model". American Journal of Physiology. Renal Physiology. 292 (5): F1345–F1353. doi:10.1152/ajprenal.00487.2006. PMC   2020516 . PMID   17299139.
  16. ↑ Wall SM (2006). "The Renal Physiology of Pendrin (SLC26A4) and Its Role in Hypertension". Epithelial Anion Transport in Health and Disease: The Role of the SLC26 Transporters Family. Novartis Foundation Symposia. Vol. 273. pp. 231–9, discussion 239–43, 261–4. doi:10.1002/0470029579.ch15. ISBN   978-0-470-02957-2. PMID   17120771.
  17. ↑ Royaux IE, Wall SM, Karniski LP, Everett LA, Suzuki K, Knepper MA, et al. (March 2001). "Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion". Proceedings of the National Academy of Sciences of the United States of America. 98 (7): 4221–4226. Bibcode:2001PNAS...98.4221R. doi: 10.1073/pnas.071516798 . PMC   31206 . PMID   11274445.
  18. ↑ Koeppen BM, Stanton BA, Swiatecka-Urban A, eds. (2024). Berne & Levy Physiology (8th ed.). Philadelphia, PA: Elsevier. ISBN   978-0-323-84790-2.
  19. ↑ Pela I, Bigozzi M, Bianchi B (June 2008). "Profound hypokalemia and hypochloremic metabolic alkalosis during thiazide therapy in a child with Pendred syndrome". Clinical Nephrology. 69 (6): 450–453. doi:10.5414/cnp69450. PMID   18538122.
  20. ↑ Kuperman DA, Lewis CC, Woodruff PG, Rodriguez MW, Yang YH, Dolganov GM, et al. (August 2005). "Dissecting asthma using focused transgenic modeling and functional genomics". The Journal of Allergy and Clinical Immunology. 116 (2): 305–311. doi:10.1016/j.jaci.2005.03.024. PMID   16083784.
  21. ↑ Zhen G, Park SW, Nguyenvu LT, Rodriguez MW, Barbeau R, Paquet AC, et al. (February 2007). "IL-13 and epidermal growth factor receptor have critical but distinct roles in epithelial cell mucin production". American Journal of Respiratory Cell and Molecular Biology. 36 (2): 244–253. doi:10.1165/rcmb.2006-0180OC. PMC   1899314 . PMID   16980555.
  22. ↑ Pedemonte N, Caci E, Sondo E, Caputo A, Rhoden K, Pfeffer U, et al. (April 2007). "Thiocyanate transport in resting and IL-4-stimulated human bronchial epithelial cells: role of pendrin and anion channels". Journal of Immunology. 178 (8): 5144–5153. doi: 10.4049/jimmunol.178.8.5144 . PMID   17404297.
  23. ↑ Nakao I, Kanaji S, Ohta S, Matsushita H, Arima K, Yuyama N, et al. (May 2008). "Identification of pendrin as a common mediator for mucus production in bronchial asthma and chronic obstructive pulmonary disease". Journal of Immunology. 180 (9): 6262–6269. doi: 10.4049/jimmunol.180.9.6262 . PMID   18424749.
  24. ↑ Nakagami Y, Favoreto S, Zhen G, Park SW, Nguyenvu LT, Kuperman DA, et al. (August 2008). "The epithelial anion transporter pendrin is induced by allergy and rhinovirus infection, regulates airway surface liquid, and increases airway reactivity and inflammation in an asthma model". Journal of Immunology. 181 (3): 2203–2210. doi:10.4049/jimmunol.181.3.2203. PMC   2491716 . PMID   18641360.

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