The physiological role of drug transporters DOI Creative Commons
Yu Liang, Siqi Li, Ligong Chen

et al.

Protein & Cell, Journal Year: 2015, Volume and Issue: 6(5), P. 334 - 350

Published: March 23, 2015

Transporters comprise the largest family of membrane proteins in human organism, including members solute carrier transporter and ATP-binding cassette families. They play pivotal roles absorption, distribution excretion xenobiotic endogenous molecules. are widely expressed various tissues routinely evaluated during process drug development approval. Over past decade, increasing evidence shows that transporters important both normal physiology disease. Currently, utilized as therapeutic targets to treat numerous diseases such diabetes, major depression, hypertension constipation. Despite steady growth field biology, more than half superfamily have little information available about their substrate(s) or physiological functions. This review outlines current research methods studies, summarizes drug-transporter interactions drug-drug drug-endogenous substrate interactions. In end, we also discuss perspective based on pathophysiological roles.

Language: Английский

Structural biology of solute carrier (SLC) membrane transport proteins DOI Open Access
Xiaoyun Bai, Trevor F. Moraes, Reinhart A.F. Reithmeier

et al.

Molecular Membrane Biology, Journal Year: 2017, Volume and Issue: 34(1-2), P. 1 - 32

Published: Feb. 17, 2017

The human solute carriers (SLCs) comprise over 400 different transporters, organized into 65 families ( http://slc.bioparadigms.org/ ) based on their sequence homology and transport function. SLCs are responsible for transporting extraordinarily diverse solutes across biological membranes, including inorganic ions, amino acids, lipids, sugars, neurotransmitters drugs. Most of these membrane proteins function as coupled symporters (co-transporters) utilizing downhill ion (H+ or Na+) gradients the driving force substrate against its concentration gradient cells. Other members work antiporters (exchangers) that typically contain a single substrate-binding site with an alternating access mode transport, while few exhibit channel-like properties. Dysfunction is correlated numerous diseases therefore they potential therapeutic drug targets. In this review, we identified all SLC crystal structures have been determined, most which from prokaryotic species. We further sorted four main groups protein folds discuss well-characterized MFS (major facilitator superfamily) LeuT (leucine transporter) folds. This review provides systematic analysis structure, molecular basis recognition mechanism action in family members.

Language: Английский

Citations

161
Intracellular pH in sperm physiology DOI
Takuya Nishigaki, José Omar, Ana Laura González‐Cota

et al.

Biochemical and Biophysical Research Communications, Journal Year: 2014, Volume and Issue: 450(3), P. 1149 - 1158

Published: June 2, 2014

Language: Английский

Citations

159
Bicarbonate transporters in corals point towards a key step in the evolution of cnidarian calcification DOI Creative Commons
Didier Zoccola, Philippe Ganot, Anthony Bertucci

et al.

Scientific Reports, Journal Year: 2015, Volume and Issue: 5(1)

Published: June 4, 2015

Abstract The bicarbonate ion (HCO 3 − ) is involved in two major physiological processes corals, biomineralization and photosynthesis, yet no molecular data on transporters are available. Here, we characterized plasma membrane-type HCO the scleractinian coral Stylophora pistillata . Eight solute carrier (SLC) genes were found genome: five homologs of mammalian-type SLC4 family members three SLC26 members. Using relative expression analysis immunostaining, analyzed cellular distribution these conducted phylogenetic analyses to determine extent conservation among cnidarian model organisms. Our suggest that SLC4γ isoform specific corals responsible for supplying site calcification. Taken together, appears be one key skeleton building which bears profound implications our understanding evolution within cnidarians.

Language: Английский

Citations

159
Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targets DOI Open Access
Iram Haq, Michael A. Gray, James P. Garnett

et al.

Thorax, Journal Year: 2015, Volume and Issue: 71(3), P. 284 - 287

Published: Dec. 30, 2015

Cystic fibrosis (CF) is a life-limiting disease characterised by recurrent respiratory infections, inflammation and lung damage. The volume composition of the airway surface liquid (ASL) are important in maintaining ciliary function, mucociliary clearance antimicrobial properties airway. In CF, these homeostatic mechanisms impaired, leading to dehydrated acidic ASL. ASL depletion CF secondary defective anion transport abnormal cystic transmembrane conductance regulator protein (CFTR). Abnormal CFTR mediated bicarbonate creates an unfavourable, environment, which impairs function alters mucus clearance. These create disordered milieu, consisting thick mucopurulent secretions chronic bacterial infection. addition CFTR, there additional ion channels transporters apical epithelium that play role homeostasis. include epithelial sodium channel (ENaC), solute carrier 26A (SLC26A) family exchangers, calcium-activated chloride channels. this review we discuss how targeting alternative could provide attractive therapeutic strategy correct underlying abnormalities evident CF.

Language: Английский

Citations

147
Pathophysiology of IBD associated diarrhea DOI Open Access
Arivarasu Natarajan Anbazhagan, Shubha Priyamvada,

Waddah A. Alrefai

et al.

Tissue Barriers, Journal Year: 2018, Volume and Issue: 6(2), P. e1463897 - e1463897

Published: April 3, 2018

Inflammatory bowel diseases broadly categorized into Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the gastrointestinal tract with increasing prevalence worldwide. The etiology is complex involves a combination genetic, environmental, immunological gut microbial factors. Recurring bloody diarrhea most prevalent debilitating symptom in IBD. pathogenesis IBD-associated multifactorial essentially an outcome mucosal damage caused by persistent inflammation resulting dysregulated intestinal ion transport, impaired epithelial barrier function increased accessibility pathogens to mucosa. Altered expression and/or transporters channels principle cause electrolyte retention water accumulation lumen leading Aberrant further contributes via leak-flux mechanism. Mucosal penetration enteric promotes dysbiosis exacerbates underlying immune system perpetuating IBD associated-tissue diarrhea. Here, we review mechanisms transport loss contributing associated

Language: Английский

Citations

142
Regulation and roles of bicarbonate transporters in cancer DOI Creative Commons
Andrej Gorbatenko,

Christina W. Olesen,

Ebbe Boedtkjer

et al.

Frontiers in Physiology, Journal Year: 2014, Volume and Issue: 5

Published: April 16, 2014

A unifying feature of solid tumors is a markedly altered pH profile compared to normal tissues. This reflects that tumors, despite completely different origins, often share several phenotypic properties with implications for intra- and extracellular pH. These include: metabolic shift in most cancer cells towards more acid-producing pathways, reflecting both oncogenic signaling the development hypoxia poorly perfused regions tumors; highly dense tumor microenvironment, reducing diffusive flux acid equivalents tissues; regulation expression activity pH-regulatory transport proteins cells. While some these have been well described recent years, great majority research this clinically important area has focused on proton transport, particular via Na+/H+-exchanger 1 (SLC9A1, NHE1) various H+ ATPases. We have, however, recently demonstrated at least under conditions, including vitro models HER2 positive breast cancer, measurements obtained directly freshly dissected human mammary bicarbonate transporters such as electroneutral Na+,HCO3--cotransporter (SLC4A7, NBCn1), are upregulated play central roles regulation. In review, we summarize discuss current knowledge regarding cancer.

Language: Английский

Citations

132
Cryo-EM structures and functional characterization of murine Slc26a9 reveal mechanism of uncoupled chloride transport DOI Creative Commons
Justin D. Walter, Marta Sawicka, Raimund Dutzler

et al.

eLife, Journal Year: 2019, Volume and Issue: 8

Published: July 24, 2019

The epithelial anion transporter SLC26A9 contributes to airway surface hydration and gastric acid production. Colocalizing with CFTR, has been proposed as a target for the treatment of cystic fibrosis. To provide molecular details its transport mechanism, we present cryo-EM structures functional characterization murine Slc26a9. These define general architecture eukaryotic SLC26 family members reveal an unusual mode oligomerization which relies predominantly on cytosolic STAS domain. Our data illustrates conformational transitions Slc26a9, supporting rapid alternate-access mechanism mediates uncoupled chloride negligible bicarbonate or sulfate permeability. structure-guided mutants illuminates properties ion path, including selective binding site located in center mobile module within transmembrane This study thus provides structural foundation understanding entire potentially facilitates their therapeutic exploitation.

Language: Английский

Citations

132
The Concise Guide toPHARMACOLOGY2013/14: Transporters DOI Creative Commons
S P H Alexander,

Helen E. Benson,

Elena Faccenda

et al.

British Journal of Pharmacology, Journal Year: 2013, Volume and Issue: 170(8), P. 1706 - 1796

Published: Dec. 1, 2013

Abstract The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties over 2000 human drug targets with their pharmacology, plus links an open access knowledgebase and ligands ( www.guidetopharmacology.org ), which more detailed views target ligand properties. full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full . Transporters are one seven major pharmacological into is divided, others being G protein‐coupled receptors, ligand‐gated ion channels, catalytic nuclear hormone receptors enzymes. These presented nomenclature guidance summary information on best available tools, alongside references suggestions for further reading. A new landscape format has easy use tables comparing related targets. It a condensed version material contemporary late 2013, in greater detail constantly updated website , superseding data previous Guides Receptors Channels. produced conjunction NC‐IUPHAR official IUPHAR classification targets, where appropriate. consolidates previously curated displayed separately IUPHAR‐DB Channels, providing permanent, citable, point‐in‐time record that will survive database updates.

Language: Английский

Citations

127
Pendred syndrome DOI
Jean-Louis Wémeau, Peter Kopp

Best Practice & Research Clinical Endocrinology & Metabolism, Journal Year: 2017, Volume and Issue: 31(2), P. 213 - 224

Published: March 1, 2017

Language: Английский

Citations

123
What is pH regulation, and why do cancer cells need it? DOI Creative Commons
Pawel Swietach

Cancer and Metastasis Reviews, Journal Year: 2019, Volume and Issue: 38(1-2), P. 5 - 15

Published: Feb. 1, 2019

Metabolism is a continuous source of acids. To keep up with desired metabolic rate, tumors must establish an adequate means clearing their acidic end-products. This homeostatic priority achieved by various buffers, enzymes, and transporters connected through the common denominator H+ ions. Whilst this complexity proportionate to importance pH control, it problematic for developing intuition tracking route taken acids, assessing relative acid-handling proteins, predicting outcomes pharmacological inhibition or genetic alteration. Here, help simplified mathematical framework, genesis cancer regulation explained in terms obstacles efficient acid venting how these are overcome specific molecules, often associated cancer. Ultimately, regulatory apparatus (i) provide lactic permeability membranes, (ii) facilitate CO2/HCO3−/H+ diffusivity across interstitium, (iii) invest form active transport that strikes favorable balance between intracellular lactate retention under energetic constraints cell, (iv) enable necessary feedback complete loop. A more informed quantitative approach understanding mandatory identifying vulnerabilities, which could be exploited as therapeutic targets.

Language: Английский

Citations

118