Molecular Basis for Cation Selectivity in Claudin-2–based Paracellular Pores: Identification of an Electrostatic Interaction Site

Yu, Alan; Cheng, Mary Hongying; Angelow, Susanne; Günzel, Dorothee; Kanzawa, Sanae A.; Schneeberger, Eveline E.; Fromm, Michael; Coalson, Rob D.

doi:10.1085/jgp.200810154

Cited by 275 publications

(260 citation statements)

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“…Previous reports have shown that the paracellular passage across TJs is temperature dependent (12,28,31), and this property may depend on the molecular dynamics of the claudin-based TJ strands. Therefore, we assessed the temperature dependency of the paracellular permeability of MDCK I-Venus-claudin-21 cell sheets for small and large cations.…”

Section: Resultsmentioning

confidence: 99%

“…With regard to the paracellular permeation of Na ϩ , the most abundant cation in the body, the physiologically estimated diameter of claudin-21's pore (ϳ5.6 Å) is smaller than the diameter of hydrated Na ϩ (7.2 Å) (39). To pass through the claudin-21-based channel, Na ϩ might be partially dehydrated, similar to the case for claudin-2-based channels (ϳ6.5 Å) (31). Moreover, evidence suggests that claudin-2 mediates paracellular water flow as well as ion permeation (24).…”

Section: Discussionmentioning

confidence: 99%

“…The electrophysiological characterization of MDCK I cell monolayers was carried out according to published methods (30,31). Venus-claudin-expressing transfectants of MDCK I cells were grown on Transwell filters (Costar; Corning Life Sciences, Acton, MA) for 7 days.…”

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confidence: 99%

“…The organic cations included methylammonium (MA), ethylammonium (EA), tetramethylammonium (TMA), tetraethylammonium (TEA), arginine (Arg), and N-methyl-D-glucamine (NMDG). The NaCl dilution potential and biionic potential were measured as described previously (31). The transepithelial conductance was calculated by passing a current and measuring the potential across the epithelial cell sheet according to Ohm's law.…”

mentioning

confidence: 99%

“…The resulting potential was corrected for the liquid junction potential, which was determined by performing analogous experiments using the method described by Alan Yu's group (31 , and the result is referred to here as "cation permeability (37°C Ϫ 4°C)." To estimate the size exclusion threshold of the temperature-dependent permeability, the cation permeability (37°C Ϫ 4°C) of MDCK I-Venus cells was subtracted from that of MDCK I-Venus-claudin-21 cells or MDCK IVenus-claudin-15 cells.…”

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confidence: 99%

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Claudin-21 Has a Paracellular Channel Role at Tight Junctions

Tanaka

Yamamoto

Kashihara

et al. 2016

Molecular and Cellular Biology

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g Claudin protein family members, of which there are at least 27 in humans and mice, polymerize to form tight junctions (TJs) between epithelial cells, in a tissue-and developmental stage-specific manner. Claudins have a paracellular barrier function. In addition, certain claudins function as paracellular channels for small ions and/or solutes by forming selective pores at the TJs, although the specific claudins involved and their functional mechanisms are still in question. Here we show for the first time that claudin-21, which is more highly expressed in the embryonic than the postnatal stages, acts as a paracellular channel for small cations, such as Na ؉ , similar to the typical channel-type claudins claudin-2 and -15. Claudin-21 also allows the paracellular passage of larger solutes. Our findings suggest that claudin-21-based TJs allow the passage of small and larger solutes by both paracellular channel-based and some additional mechanisms. Epithelial cell sheets form and cover every compartment of the body. Homeostasis is specifically maintained for organ and tissue function in each compartment. To create sheets with a barrier function, epithelial cells adhere to each other side by side through well-organized cell-cell adhesion systems (1), such as tight junctions (TJs), which maintain distinct environments by blocking the free exchange of molecules across the cell sheet (2, 3). Accumulating evidence indicates that the molecular strands that form the TJ barriers are composed primarily of polymerized claudins, which are adhesion molecules containing four transmembrane helices (2, 4). The claudins both create the paracellular barrier and determine which ions and/or molecules can selectively cross it (5-7).The claudins comprise a large gene family with at least 27 members, in humans or mice, that have distinct expression patterns and properties (2,3,8). Epithelial cells generally express multiple types of claudins; the particular claudin combination expressed appears to determine the specific properties of each TJbased paracellular permselective barrier (9-22). Two categories of claudins have been proposed, namely, the paracellular barrier type and the paracellular channel type, based on the transepithelial electrical resistance (TER) or on the cation and/or anion permeability of many epithelial cell lines (5, 7). Among some claudins characterized as channel-type claudins, such as claudin-2, -7, -10, -15, -16, and -17, claudin-2 and -15 have been studied extensively with respect to specific ions and water (9-11, 14, 17, 20, 21, 23, 24).The structure of claudin-15 was recently analyzed; this analysis revealed that two extracellular segments form a unique ␤ sheet domain fixed to a transmembrane four-helix bundle by a W-LW claudin consensus motif (25,26). The high-resolution structure of claudin-15 suggests that a ␤-barrel pore created by eight claudin molecules in the region between two cells can form a paracellular channel, which is regulated by charged residues on the claudins' extracellular domains.Although ...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Claudin-21 Has a Paracellular Channel Role at Tight Junctions

Tanaka

Yamamoto

Kashihara

et al. 2016

Molecular and Cellular Biology

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Epithelia and Gastrointestinal Function

Turner

2015

Yamada' S Textbook of Gastroenterology

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Claudins and Other Tight Junction Proteins

Günzel¹,

Fromm²

2012

Comprehensive Physiology

310

276

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Epithelial transport relies on the proper function and regulation of the tight junction (TJ), other-wise uncontrolled paracellular leakage of solutes and water would occur. They also act as a fence against mixing of membrane proteins of the apical and basolateral side. The proteins determining paracellular transport consist of four transmembrane regions, intracellular N and C terminals, one intracellular and two extracellular loops (ECLs). The ECLs interact laterally and with counterparts of the neighboring cell and by this achieve a general sealing function. Two TJ protein families can be distinguished, claudins, comprising 27 members in mammals, and TJ-associated MARVEL proteins (TAMP), comprising occludin, tricellulin, and MarvelD3. They are linked to a multitude of TJ-associated regulatory and scaffolding proteins. The major TJ proteins are classified according to the physiological role they play in enabling or preventing paracellular transport. Many TJ proteins have sealing functions (claudins 1, 3, 5, 11, 14, 19, and tricellulin). In contrast, a significant number of claudins form channels across TJs which feature selectivity for cations (claudins 2, 10b, and 15), anions (claudin-10a and -17), or are permeable to water (claudin-2). For several TJ proteins, function is yet unclear as their effects on epithelial barriers are inconsistent (claudins 4, 7, 8, 16, and occludin). TJs undergo physiological and pathophysiological regulation by altering protein composition or abundance. Major pathophysiological conditions which involve changes in TJ protein composition are (1) effects of pathogens binding to TJ proteins, (2) altered TJ protein composition during inflammation and infection, and (3) altered TJ protein expression in cancers.

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Molecular Basis for Cation Selectivity in Claudin-2–based Paracellular Pores: Identification of an Electrostatic Interaction Site

Cited by 275 publications

References 48 publications

Claudin-21 Has a Paracellular Channel Role at Tight Junctions

Claudin-21 Has a Paracellular Channel Role at Tight Junctions

Epithelia and Gastrointestinal Function

Claudins and Other Tight Junction Proteins

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