Claudin-21 Has a Paracellular Channel Role at Tight Junctions

Abstract

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 ...

Tight junction strand formation by claudin‐10 isoforms and claudin‐10a/‐10b chimeras

“…Some claudins are able to confer ion selectivity to this barrier; in other words, they form paracellular ion channels that traverse TJ strands. Thus, claudin‐2, ‐10b, ‐15, and ‐21 form paracellular cation channels, and claudin‐10a and ‐17 form anion channels . In many tissues, these paracellular channels are an essential component of transepithelial transport: if these channels are defective, transcellular transport, driven by transport proteins within the cell membrane, also comes to a standstill (for a review, see Ref.…”

“…Thus, claudin-2, -10b, -15, and -21 form paracellular cation channels, and claudin-10a and -17 form anion channels. [12][13][14][15][16][17] In many tissues, these paracellular channels are an essential component of transepithelial transport: if these channels are defective, transcellular transport, driven by transport proteins within the cell membrane, also comes to a standstill (for a review, see Ref. 18).…”

The mucosal barrier at a glance

“…The core protein components of the tight junction support paracellular flux through two distinct routes, termed the pore and leak pathways Turner, 2009). The pore pathway is a high-capacity route that is selective in terms of size and charge, with the maximal diameters of transported molecules ranging from approximately ∼5 Å to ∼10 Å (Krug et al, 2012;Tanaka et al, 2016;Van Itallie et al, 2008;Yu et al, 2009). Although less-well characterized, the best available evidence suggests that the complementary leak pathway supports the paracellular flux of molecules with diameters up to 125 Å and is not charge selective, but has a limited capacity (Buschmann et al, 2013;Turner, 2009).…”

MicroRNAs in intestinal barrier function, inflammatory bowel disease and related cancers — their effects and therapeutic potentials

“…Organized in a single layer, IECs are linked by three types of junctions, namely, from apical to basal, tight junctions, adherens junctions and desmosomes. Tight junctions are implicated in blocking the transit of bacteria and food while facilitating paracellular flux through the pore pathway and the leak pathway [8]. Chronic, enhanced inflammation can damage IB, allowing unwanted bacteria and molecules to cross IB and further exacerbate the immune response, depending on the quality of mucosal layer and tight junctions, the composition of the microbiota, and ultimately the genotype of each individual.…”