Electroneutral cation-Cl− cotransporters compose a family of solute carriers in which cation (Na+ or K+) movement through the plasma membrane is always accompanied by Cl− in a 1:1 stoichiometry. Se...

https://www.physiology.org/doi/pdf/10.1152/physrev.00011.2004

Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters

Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting β polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) α and β] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

/pdf/genome-wide-association-analyses-identify-18-new-loci-588r33zp0r.pdf

Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability.

Drug transport in the central nervous system is highly regulated not only by the blood-brain and the blood-cerebrospinal fluid barriers but also in brain parenchyma. The novel localization of drug transporters in brain parenchyma cells, such as microglia and astrocytes, suggest a reconsideration of the present conceptualization of brain barriers as it relates to drug transport. That is, the cellular membranes of parenchyma cells act as a second "barrier" to drug permeability and express transporters whose properties appear similar to those localized at the conventional brain barriers. This review will focus on the molecular characteristics, localization, and substrate specificities of several classes of well known membrane drug transporters (i.e., the organic cation, organic anion, nucleoside, P-glycoprotein, and multidrug resistance proteins) in the brain. Comparisons to similar transporters localized within the peripheral system and clinical implications of the functional expression of specific drug transport families will be discussed when appropriate. Nutrient and neurotransmitter transporters, whose characteristics have been reviewed extensively elsewhere, will not be considered in this review.

Drug Transporters in the Central Nervous System: Brain Barriers and Brain Parenchyma Considerations

Stanniocalcin (STC) is a glycoprotein hormone first identified in bony fishes where it counteracts hypercalcemia by inhibiting gill calcium uptake and stimulating renal inorganic phosphate (Pi) reabsorption. Human STC (hSTC) has recently been cloned and sequenced and is highly homologous to the fish hormone at the amino acid level. The objective of this study was to examine the possible effects of hSTC on electrolyte homeostasis and renal function in the rat. Recombinant hSTC was expressed in bacteria and purified by metal-ion affinity chromatography and reverse-phase high performance liquid chromatography. Anesthetized animals were given bolus infusions of 1, 5, or 10 nmol hSTC per kilogram of body weight. Control animals received solvent alone. The most effective dosage was 5 nmol/kg, which caused significant reductions in both absolute and fractional phosphate excretion in comparison with control rats. The hSTC had no effect on the renal excretion of other ions, the glomerular filtration rate, renal blood flow, blood pressure, or plasma electrolytes (Na+, K+, Ca2+, Pi, Mg/+). The maximum effect of hSTC on phosphate excretion was observed 60-80 minutes postinjection. Lesser effects were obtained with higher and lower dosages of hormone. When renal cortical brush-border membrane vesicles were isolated from control and hormone-treated animals 80 minutes postinjection, the rate of Na+/Pi cotransport was found to be 40% higher in vesicles from hormone-treated animals (p < 0.01; 5 nmol hSTC/kg). Together, the renal clearance and membrane vesicle data indicate that hSTC participates in the renal regulation of Pi homeostasis in mammals.

https://asbmr.onlinelibrary.wiley.com/doi/pdf/10.1359/jbmr.1997.12.2.165

Human Stanniocalcin Inhibits Renal Phosphate Excretion in the Rat

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two factors that share amino acid sequence homology and act via a common receptor. In tetrapods, PTH is the main endocrine factor acting in bone and kidney to regulate calcium and phosphate. PTHrP is an essential paracrine developmental factor present in many tissues and is involved in the regulation of ossification, mammary gland development, muscle relaxation, and other functions. Fish apparently lack an equivalent of the parathyroid gland and were long thought to be devoid of PTH. Only in recent years has the existence of PTH-like peptides and their receptors in fish been firmly established. Two forms of PTH, two of PTHrP, and a protein with intermediate characteristics designated PTH-L are encoded by separate genes in teleost fish. Three receptors encoded by separate genes in fish mediate PTH/PTHrP actions, whereas only two receptors have so far been found in terrestrial vertebrates. PTHrP has been more intensively studied than PTH, from lampreys to advanced teleosts. It is expressed in many tissues and is present in high concentration in fish blood. Administration of this peptide alters calcium metabolism and has marked effects on associated gene expression and enzyme activity in vivo and in vitro. This review provides a comprehensive overview of the physiological roles, distribution, and molecular relationships of the piscine PTH-like peptides.

/pdf/the-parathyroid-hormone-family-of-peptides-structure-tissue-44rlfxndwy.pdf

The parathyroid hormone family of peptides: structure, tissue distribution, regulation, and potential functional roles in calcium and phosphate balance in fish

The relationship between transepithelial Na+ and Cl- active transport from the mucosal toward the serosal surface was studied by ion substitution experiments in the isolated, perfused urinary bladder of the winter flounder, Pseudopleuronectes americanus. The tissue behaves as a simple ohmic resistance of about 1000 ohm-cm2 which was not significantly changed by perfusion of the lumen (mucosal surface) with Na-free or Cl-free solutions. Trans-epithelial electrical potential difference and short-circuit current were reversed (mucosa positive to negative) by Cl-free perfusion but unaltered by Na-free medium. Short-circuit current did not agree with isotopically measured net Na+ and Cl- flux in either control or ion-substituted medium. Cl-free perfusion depressed net Na+ flux more than 50% and a similar effect was seen on net Cl- flux upon Na-free perfusion. A kinetic analysis of the relationship of Na+ or Cl- flux to the concentration of Na+ or Cl- in the perfusate in the presence and absence of Cl- or Na+, respectively, indicated that Cl-free medium acted as a non-competitive inhibitor of Na+ transport, and the effect of Na-free medium on Cl- transport could be interpreted similarly. This inter-dependence of Na+ and Cl- transport was taken as an indication of co-transport of these two ions. Amiloride (10(-4) M) seemed to inhibit a component of Na flux distinct from the Cl-dependent flux. It had no effect on Cl- transport.

Interdependence of active Na+ and Cl− transport by the isolated urinary bladder of the teleost, Pseudopleuronectes americanus

SUMMARY The effect of physicochemical stress on organic anion transport across the
vertebrate blood–cerebrospinal fluid (CSF) barrier in the presence and
absence of an endogenous cytoprotectant, trimethylamine oxide (TMAO), was
investigated in isolated IVth choroid plexus (CP) of spiny dogfish shark
( Squalus acanthias ), an animal with naturally high levels of TMAO
(∼70 mmol l –1 ). Active transepithelial absorption of the
organic anion, 2,4-dichlorophenoxyacetic acid (2,4-D), by IVth CP mounted in
Ussing chambers was measured after in vitro stress, and a marker for
the cellular stress response, inducible heat shock protein 70 (Hsp70), was
assayed by immunoblot analysis. Transient heat stress (a shift from the normal
13.5°C to 23.5°C for 1 h) decreased 2,4-D transport by ∼66%;
however, the same stress minus TMAO (isosmotic replacement with urea) had no
effect on transport rate. In the absence of TMAO, stress-induced Hsp70
accumulation was more than double that seen in the presence of TMAO. Likewise,
exposure to 50 μmol l –1 Zn for 6 h induced a twofold
greater Hsp70 accumulation in the absence of TMAO than in its presence, and
the higher Hsp70 level was associated with a higher 2,4-D transport rate. Heat
stress and 50 μmol l –1 Zn also induced more pronounced
increases in Hsp70 mRNA in the absence of TMAO. Thus, the cellular stress
response can significantly alter CP organic anion transport capacity, and an
endogenous osmolyte can suppress that response.

/pdf/trimethylamine-oxide-suppresses-stress-induced-alteration-of-w68uca76v6.pdf

Trimethylamine oxide suppresses stress-induced alteration of organic anion transport in choroid plexus.

Birds are uricotelic, and because they excrete urate by renal tubular secretion, they provide a convenient model for examination of this process. Primary monolayer cultures of the isolated renal proximal tubule epithelium from the domestic chicken, Gallus gallus L., were mounted in Ussing chambers where several substrates/inhibitors of renal organic anion transporters were tested for the sidedness and specificity of their effects on transepithelial urate transport. Transepithelial electrical resistance, electrical potential and sodium-dependent glucose current were monitored to detect nonspecific effects. Under control short-circuited conditions the ratio of unidirectional fluxes of [(14)C]urate was found to be 3:1. Active net secretion was specifically inhibited by 1 mmol l(-1) probenecid and 10 mmol l(-1) para-aminohippuric acid (PAH). Bromocresol Green, cimetidine, nocodozole, cytochalasin D and ouabain also inhibited secretion but were toxic. Interstitial-side lithium (5 mmol l(-1)) and glutarate (1 mmol l(-1)) specifically blocked transport, but 10-100 micromol l(-1) glutarate had no effect. Interstitial estrone sulfate (ES) stimulated urate secretion at 10 micromol l(-1) but was inhibitory at 500 micromol l(-1). Active PAH secretion (5:1 flux ratio) was inhibited 34% by 330 micromol l(-1) urate. ES (500 micromol l(-1)) blocked the remainder. From the lumen side, glucose-free, Cl(-)-free and high K(+) (30 mmol l(-1)) solutions, or an alkaline pH of 7.7 had no effect on urate transport and neither did several compounds known to be uricosuric. Lumen-side methotrexate (500 micromol l(-1)) and MK571 (20 micromol l(-1)) strongly inhibited urate secretion. MK571 had no effect from the interstitial side. RT-PCR revealed mRNA for OAT1-, OAT3-, MRP2- and MRP4-like organic anion transporters in chicken proximal epithelium.

J. Larry Renfro

Papers

Human Stanniocalcin Inhibits Renal Phosphate Excretion in the Rat

The parathyroid hormone family of peptides: structure, tissue distribution, regulation, and potential functional roles in calcium and phosphate balance in fish

Interdependence of active Na+ and Cl− transport by the isolated urinary bladder of the teleost, Pseudopleuronectes americanus

Trimethylamine oxide suppresses stress-induced alteration of organic anion transport in choroid plexus.

Transepithelial urate transport by avian renal proximal tubule epithelium in primary culture.