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Getting Molecules across Cellular Membranes: Transporters, Channels and Pores

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 10618

Special Issue Editor


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Guest Editor
Department of Biology and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabrück, D-49076 Osnabrück, Germany
Interests: membrane proteins; regulated cell death; single molecule imaging; high resolution microscopy; atomic force microscopy
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Special Issue Information

Dear Colleagues,

Cellular membranes are central for maintaining cellular integrity and homeostasis, as well as for intra- and inter-cellular communication and exchange with the environment. They are composed of lipid bilayers that act as a tight, impermeable barrier and allow only the passive diffusion of small and moderately polar molecules. Yet, there is a constant flux of ions and bigger molecules across the plasma membrane (PM) and intracellular membranes delimiting organelles, such as mitochondria. To ensure the selective and controlled passage of substances, including large nutrients and signalling proteins, cellular membranes rely on the presence of transmembrane proteins. These include transporters, channels and pores. Transporters require conformational changes to allow the solute bound on one site to exit the opposite site of the membrane. In contrast, channels control solute traffic by stabilizing an open or closed conformation. Finally, pores are defined as open structures generally allowing the non-selective passage of molecules smaller than the pore's size. Interestingly, bacteria and viruses make use of pore-forming toxins (PFTs) to create pores on the PM of target cells to allow the intracellular transport of toxins or genetic material. However, cells can also create pores on the membranes of pathogens to kill them and, importantly, on their own membranes to allow the passage of signalling molecules that initiate downstream pathways, such as inflammation and cell death.

In this Special Issue, we will welcome both reviews and research articles that provide an overview of the current knowledge about the molecular mechanisms, the structure and the function of different peptides and proteins that channel molecules across cellular membranes. We will also welcome contributions highlighting biomedical applications of these proteins, as well as innovative methods for their characterization, including, but not limited to, single-molecule fluorescence spectroscopy and microscopy and cryo-EM.

Dr. Katia Cosentino
Guest Editor

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Keywords

  • membrane proteins
  • pore forming proteins
  • channels
  • transporters
  • pumps
  • membrane pores
  • pore forming toxins
  • antimicrobial peptides
  • cell death programs
  • inflammation
  • patch clamp
  • single molecule fluorescence spectroscopy and microscopy
  • cryo-EM

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Published Papers (3 papers)

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Research

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18 pages, 3657 KiB  
Article
Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin
by Anna Hucke, Rita Schröter, Cecilia Ceresa, Alessia Chiorazzi, Annalisa Canta, Sara Semperboni, Paola Marmiroli, Guido Cavaletti, Burkhard Gess and Giuliano Ciarimboli
Int. J. Mol. Sci. 2023, 24(14), 11486; https://doi.org/10.3390/ijms241411486 - 14 Jul 2023
Cited by 2 | Viewed by 1276
Abstract
Cisplatin (CDDP) is an efficient chemotherapeutic agent broadly used to treat solid cancers. Chemotherapy with CDDP can cause significant unwanted side effects such as renal toxicity and peripheral neurotoxicity. CDDP is a substrate of organic cation transporters (OCT), transporters that are highly expressed [...] Read more.
Cisplatin (CDDP) is an efficient chemotherapeutic agent broadly used to treat solid cancers. Chemotherapy with CDDP can cause significant unwanted side effects such as renal toxicity and peripheral neurotoxicity. CDDP is a substrate of organic cation transporters (OCT), transporters that are highly expressed in renal tissue. Therefore, CDDP uptake by OCT may play a role in causing unwanted toxicities of CDDP anticancer treatment. In this study, the contribution of the mouse OCT2 (mOCT2) to CDDP nephro- and peripheral neurotoxicity was investigated by comparing the effects of cyclic treatment with low doses of CDDP on renal and neurological functions in wild-type (WT) mice and mice with genetic deletion of OCT2 (OCT2−/− mice). This CDDP treatment protocol caused significant impairment of kidneys and peripherical neurological functions in WT mice. These effects were significantly reduced in OCT2−/− mice, however, less profoundly than what was previously measured in mice with genetic deletion of both OCT1 and 2 (OCT1-2−/− mice). Comparing the apparent affinities (IC50) of mOCT1 and mOCT2 for CDDP, the mOCT1 displayed a higher affinity for CDDP than the mOCT2 (IC50: 9 and 558 µM, respectively). Also, cellular toxicity induced by incubation with 100 µM CDDP was more pronounced in cells stably expressing mOCT1 than in cells expressing mOCT2. Therefore, in mice, CDDP uptake by both OCT1 and 2 contributes to the development of CDDP undesired side effects. OCT seem to be suitable targets for establishing treatment protocols aimed at decreasing unwanted CDDP toxicity and improving anticancer treatment with CDDP. Full article
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Review

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18 pages, 2805 KiB  
Review
The Many Faces of MLKL, the Executor of Necroptosis
by Veronica Martinez-Osorio, Yasmin Abdelwahab and Uris Ros
Int. J. Mol. Sci. 2023, 24(12), 10108; https://doi.org/10.3390/ijms241210108 - 14 Jun 2023
Cited by 10 | Viewed by 3727
Abstract
Necroptosis is a recently discovered form of regulated cell death characterized by the disruption of plasma membrane integrity and the release of intracellular content. Mixed lineage kinase domain-like (MLKL) protein is the main player of this cell death pathway as it mediates the [...] Read more.
Necroptosis is a recently discovered form of regulated cell death characterized by the disruption of plasma membrane integrity and the release of intracellular content. Mixed lineage kinase domain-like (MLKL) protein is the main player of this cell death pathway as it mediates the final step of plasma membrane permeabilization. Despite the significant progress in our knowledge of the necroptotic pathway and MLKL biology, the precise mechanism of how MLKL functions remain unclear. To understand in what way MLKL executes necroptosis, it is crucial to decipher how the molecular machinery of regulated cell death is activated in response to different stimuli or stressors. It is also indispensable to unveiling the structural elements of MLKL and the cellular players that are required for its regulation. In this review, we discuss the key steps that lead to MLKL activation, possible models that explain how it becomes the death executor in necroptosis, and its emerging alternative functions. We also summarize the current knowledge about the role of MLKL in human disease and provide an overview of existing strategies aimed at developing new inhibitors that target MLKL for necroptosis intervention. Full article
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27 pages, 3201 KiB  
Review
Pore-Forming Proteins: From Pore Assembly to Structure by Quantitative Single-Molecule Imaging
by Eleonora Margheritis, Shirin Kappelhoff and Katia Cosentino
Int. J. Mol. Sci. 2023, 24(5), 4528; https://doi.org/10.3390/ijms24054528 - 25 Feb 2023
Cited by 3 | Viewed by 5153
Abstract
Pore-forming proteins (PFPs) play a central role in many biological processes related to infection, immunity, cancer, and neurodegeneration. A common feature of PFPs is their ability to form pores that disrupt the membrane permeability barrier and ion homeostasis and generally induce cell death. [...] Read more.
Pore-forming proteins (PFPs) play a central role in many biological processes related to infection, immunity, cancer, and neurodegeneration. A common feature of PFPs is their ability to form pores that disrupt the membrane permeability barrier and ion homeostasis and generally induce cell death. Some PFPs are part of the genetically encoded machinery of eukaryotic cells that are activated against infection by pathogens or in physiological programs to carry out regulated cell death. PFPs organize into supramolecular transmembrane complexes that perforate membranes through a multistep process involving membrane insertion, protein oligomerization, and finally pore formation. However, the exact mechanism of pore formation varies from PFP to PFP, resulting in different pore structures with different functionalities. Here, we review recent insights into the molecular mechanisms by which PFPs permeabilize membranes and recent methodological advances in their characterization in artificial and cellular membranes. In particular, we focus on single-molecule imaging techniques as powerful tools to unravel the molecular mechanistic details of pore assembly that are often obscured by ensemble measurements, and to determine pore structure and functionality. Uncovering the mechanistic elements of pore formation is critical for understanding the physiological role of PFPs and developing therapeutic approaches. Full article
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