Targeting ion channels in cystic fibrosis

Mall, Marcus; Galietta, Luis J. V.

doi:10.1016/j.jcf.2015.06.002

Cited by 127 publications

(114 citation statements)

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“…Additionally, there is an increased activity of the ENaC in CF airways that has also been linked to CF pathogenesis (Boucher, 2007a; Mall and Galietta, 2015). Lack of CFTR function also leads to chronic respiratory infections, pancreatic dysfunction, intestinal obstruction disorders, liver dysfunction, and infertility.…”

Section: Mucus In Disease Statesmentioning

confidence: 99%

Physicochemical properties of mucus and their impact on transmucosal drug delivery

Ghosh

2017

International Journal of Pharmaceutics

360

273

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Mucus is a selective barrier to particles and molecules, preventing penetration to the epithelial surface of mucosal tissues. Significant advances in transmucosal drug delivery have recently been made and have emphasized that an understanding of the basic structure, viscoelastic properties, and interactions of mucus is of great value in the design of efficient drug delivery systems. Mucins, the primary non-aqueous component of mucus, are polymers carrying a complex and heterogeneous structure with domains that undergo a variety of molecular interactions, such as hydrophilic/hydrophobic, hydrogen bonds and electrostatic interactions. These properties are directly relevant to the numerous mucin-associated diseases, as well as delivering drugs across the mucus barrier. Therefore, in this review we discuss regional differences in mucus composition, mucus physicochemical properties, such as pore size, viscoelasticity, pH, and ionic strength. These factors are also discussed with respect to changes in mucus properties as a function of disease state. Collectively, the review seeks to provide a state of the art roadmap for researchers who must contend with this critical barrier to drug delivery.

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Section: Mucus In Disease Statesmentioning

confidence: 99%

Physicochemical properties of mucus and their impact on transmucosal drug delivery

Ghosh

2017

International Journal of Pharmaceutics

360

273

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“…Bypass therapy has previously involved the activation of chloride channels other than CFTR 44 , but anionophores could provide a novel variant acting independently of endogenous proteins.…”

Section: Therapeutic Potential Of Anionophores In Cfmentioning

confidence: 99%

Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

Valkenier

Judd³

et al. 2015

Nature Chem

151

160

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The transport of anions across cell membranes has become an important goal for supramolecular chemistry [1][2][3][4] . It is well-known that cation carriers (cationophores) can serve as antibiotics and toxins 5,6 , and it seems likely that anion carriers might also show useful biological activity. However, suitable anionophores have only recently become available 7-10 , and the nature of their biological effects is still in question. A particular hope is that anionophores might be used to replace the activity of endogenous anion channels which are missing or defective 11,2 . Such deficiencies underlie a number of medical conditions including Best disease, Startle disease, Bartter's syndrome and, most notably, the widespread lifeshortening genetic disease cystic fibrosis (CF) 12,13 .If anionophores are to be used to treat these "channelopathies", it must be shown that they can be delivered to cells in sufficient quantities to produce substantial effects, of the same order of magnitude as endogenous anion channels, and that these quantities are not toxic to the cells. However, while a wide variety of anionophores have been studied in synthetic membranes (principally large unilamellar vesicles, or LUVs), the range of systems subjected to biological investigations is still quite limited. Moreover, from the point of view of CF treatment, the results thus far have been mixed. On the positive side, a few systems have been tested in whole cells, epithelia or (in one case) genetically modified mice 14 , using electrophysiological methods such as patch-clamp and Ussing chamber, and shown to induce anion conduction without obvious toxic effects. These anionophores include synthetic 3 peptides conceptually related to natural anion channels 11,[15][16][17] , as well as the steroid-based system 1 from the authors' laboratory 18 , and other small organic molecules 14,19,20 .Less encouragingly, a number of molecules showing anion transport in LUVs have tested positive for anti-cancer cytotoxicity (potentially valuable, but incompatible with CF treatment) 8,[21][22][23][24][25] . Many of these systems, including the well-studied prodigiosin 2 26 , transport protons as well as anions 8,[21][22][23] . Intracellular acidification can lead to apoptosis 26 , so in these cases proton transport could underlie toxicity. On the other hand, a recent study on calixpyrroles 3 suggested that anion transport as such could be cytotoxic 25 . As the transport activity of 3 was only weak, this raises the concern that powerful anionophores might be highly toxic and thus unsuitable for CF treatment. Thus far the only biological testing of these "1,5-diaxial" systems has been the early study on 1, referred to above 18 . The assay involved the application of 1 to the apical membrane of oriented Madin Darby canine kidney cell (MDCK) epithelia, mounted in an Ussing chamber, and measurement of the resulting electrical current caused by Cl − transport. The methodology is well-established, but not so convenient for screening large numbers of compounds.Mor...

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“…26 Evidence of interplay between the mechanisms regulating of CFTR and ENaC surface density has arisen from data showing the concomitant and reciprocal regulation of these channels' activities (reviewed in ref. 27). In most epithelial tissues, CFTR activity downregulates ENaC and ENaC activation promotes CFTR activity.…”

Section: Regulation Of Enac Density At the Cell Surface By Rab Gtpasesmentioning

confidence: 99%

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

Farinha

Matos

2017

Small GTPases

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The amount of ion channels and transporters present at the plasma membrane is a crucial component of the overall regulation of ion transport. The number of channels present result from an intricate network of proteins that controls the late events of channel trafficking, such as endocytosis, recycling and targeting to lysosomal degradation. Small GTPases of the Rab family are key players in these processes thus contributing to regulation of fluid secretion and ion homeostasis. In epithelia, this involves mainly the balance between the chloride channel CFTR and the sodium channel ENaC, whose misfunction is a hallmark of cystic fibrosis -the commonest recessive disorder in Caucasians. Here, we review the role of GTPases in regulating trafficking of ion channels and transporters, comparing what is known for CFTR and ENaC with other types of channels. We also discuss how feasible would be to target the Rab machinery to handle a disorder such as CF. Trafficking and Rab proteinsRegulation of ion and solute transport at the membrane of cells depends on the balance between the function of each channel or transporter and on the number of molecules present. 1 The latter is regulated by the protein trafficking machinery, which controls the process through which a membrane protein is delivered from its place of synthesis -the membrane of the endoplasmic reticulum -to its final destination -the plasma membrane (PM). Besides these anterograde trafficking pathways, channels and transporters also undergo endocytosis followed by either recycling to the PM or targeting to the lysosomal compartment. These late trafficking events are controlled by several protein partners, that include protein kinases, myosins and small GTPases, among which Rab proteins. 1 Rab GTPases form the biggest subfamily of the Ras superfamily of small GTPases. As most members of this superfamily, they function as molecular switches alternating between 2 conformational status -a GTP-bound active form and a GDP-bound inactive form. 2,3 The human subfamily contains more than 60 members that reversibly associate with different intracellular membranes, due to their post-translational modification with geranylgeranyl groups. 4 This association with membranes promotes interactions with other components of the trafficking machinery, such as coat components, motor proteins and SNAREs. 2 These characteristics make them relevant players in the control of membrane identity, in vesicle formation, motility and function, regulating the trafficking of many different classes of proteins, among which channels and transporters. 5

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Targeting ion channels in cystic fibrosis

Cited by 127 publications

References 136 publications

Physicochemical properties of mucus and their impact on transmucosal drug delivery

Physicochemical properties of mucus and their impact on transmucosal drug delivery

Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

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