Membrane Transport across Polarized Epithelia

García-Castillo, María; Chinnapen, Daniel J.‐F.; Lencer, Wayne I.

doi:10.1101/cshperspect.a027912

Cited by 51 publications

(48 citation statements)

References 175 publications

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“…The protein composition of the microvillar membrane is primarily determined by sorting and delivery pathways during membrane trafficking (Apodaca et al, 2012;Garcia-Castillo et al, 2017). It is believed that the unmasked FERM domain of ezrin engages the cytoplasmic tails of a number of membrane proteins and this might occur directly or through additional scaffolding proteins (Viswanatha et al, 2013).…”

Section: Regulation Of Membrane Protein Compositionmentioning

confidence: 99%

Regulation of actin-based apical structures on epithelial cells

Pelaseyed

Bretscher

2018

Journal of Cell Science

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Cells of transporting epithelia are characterized by the presence of abundant F-actin-based microvilli on their apical surfaces. Likewise, auditory hair cells have highly reproducible rows of apical stereocilia (giant microvilli) that convert mechanical sound into an electrical signal. Analysis of mutations in deaf patients has highlighted the critical components of tip links between stereocilia, and related structures that contribute to the organization of microvilli on epithelial cells have been found. Ezrin/radixin/moesin (ERM) proteins, which are activated by phosphorylation, provide a critical link between the plasma membrane and underlying actin cytoskeleton in surface structures. Here, we outline recent insights into how microvilli and stereocilia are built, and the roles of tip links. Furthermore, we highlight how ezrin is locally regulated by phosphorylation, and that this is necessary to maintain polarity. Localized phosphorylation is achieved through an intricate coincidence detection mechanism that requires the membrane lipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] and the apically localized ezrin kinase, lymphocyteoriented kinase (LOK, also known as STK10) or Ste20-like kinase (SLK). We also discuss how ezrin-binding scaffolding proteins regulate microvilli and how, despite these significant advances, it remains to be discovered how the cell polarity program ultimately interfaces with these processes.

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Section: Regulation Of Membrane Protein Compositionmentioning

confidence: 99%

Regulation of actin-based apical structures on epithelial cells

Pelaseyed

Bretscher

2018

Journal of Cell Science

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“…immunoglobulins in the neonate, 9 and has been exploited to achieve transcellular transport of glucagon-like peptide 1 across epithelial cells. 10,11 Ethylenediaminetetraacetic acid (EDTA; Figure 1) is a widely studied paracellular-acting PE by virtue of its ability to sequester divalent metal cations, 12 and it is characterized as a first generation tight junction (TJ) opener. 6,13 TJs are multimolecular protein complexes situated between adjacent enterocytes, strongly attaching them to one another so that only passage of water and low molecular weight solutes is permitted.…”

Section: Introductionmentioning

confidence: 99%

Probing paracellular -versustranscellular tissue barrier permeability using a gut mucosal explant culture system

Danielsen

Hansen

2019

Tissue Barriers

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Intestinal permeation enhancers (PEs), i.e. agents improving oral delivery of therapeutic drugs with poor bioavailability, may typically act by two principally different mechanisms: to increase either transcellular -or paracellular passage across the epithelium. With the aim to define these different modes of action in a small intestinal mucosal explant system, the transcellular-acting PE sodium dodecyl sulfate (SDS) was compared to the paracellular-acting PE ethylenediaminetetraacetic acid (EDTA), using several fluorescent polarand lipophilic probes. Here, SDS rendered the enterocyte cell membranes leaky for the relatively small polar tracers Lucifer yellow and a 3 kD Texas red-conjugated dextran, but most conspicuously SDS blocked constitutive endocytosis from the brush border. In contrast, the main action of EDTA was to increase paracellular passage across the epithelium of both polar probes, including 10and 70 kDa dextrans and lipophilic probes, visualized by distinct stripy lateral staining of enterocytes and/or accumulation in the lamina propria. In addition, EDTA caused a loss of epithelial cell polarity by opening tight junctions for diffusion of domain-specific basolateral/apical cell membrane protein markers into the opposite domains. By transmission electron microscopy, SDS caused the formation of vacuoles and vesicle-like structures at the lateral cell membranes. In contrast, EDTA led to a bulging of the whole enterocyte apex, resulting in a "cobblestone" appearance of the epithelium, probably caused by an extreme contraction of the perijunctional actomyosin ring. We conclude that the mucosal explant system is a convenient model for predicting transcellular/paracellular modes of action of novel prospective PEs. ARTICLE HISTORYIntestinal permeation enhancers (PEs); ethylenediaminetetraacetic acid (EDTA); sodium dodecyl sulphate (SDS); small intestine; enterocyte; brush border CONTACT E. Michael Danielsen

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“…Similarly, paracellular transport 38 by modification of tight junctions might also show a dependence on size. On the other hand, transcytosis 39 , mediated by endosomal vesicle transport, would likely be less influenced by size. Transcytosis has previously been recognized as a potential mechanism for transport of drugs and large particles across polarized cell layers.e.g.…”

Section: Discussionmentioning

confidence: 99%

Active Transport of Peptides Across the Intact Human Tympanic Membrane

Kurabi

Noack

Bernhardt

et al. 2018

Sci Rep

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We previously identified peptides that are actively transported across the intact tympanic membrane (TM) of rats with infected middle ears. To assess the possibility that this transport would also occur across the human TM, we first developed and validated an assay to evaluate transport in vitro using fragments of the TM. Using this assay, we demonstrated the ability of phage bearing a TM-transiting peptide to cross freshly dissected TM fragments from infected rats or from uninfected rats, guinea pigs and rabbits. We then evaluated transport across fragments of the human TM that were discarded during otologic surgery. Human trans-TM transport was similar to that seen in the animal species. Finally, we found that free peptide, unconnected to phage, was transported across the TM at a rate comparable to that seen for peptide-bearing phage. These studies provide evidence supporting the concept of peptide-mediated drug delivery across the intact TM and into the middle ears of patients.

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Membrane Transport across Polarized Epithelia

Cited by 51 publications

References 175 publications

Regulation of actin-based apical structures on epithelial cells

Regulation of actin-based apical structures on epithelial cells

Probing paracellular -versustranscellular tissue barrier permeability using a gut mucosal explant culture system

Active Transport of Peptides Across the Intact Human Tympanic Membrane

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