Mechanistic ion channel interactions in red cells of patients with Gárdos channelopathy
| Autor: | Raffaella Colombatti, Julia Jansen, Lars Kaestner, Laura Hertz, Min Qiao, Paola Bianchi, Xijia Wang, Anna Zaninoni, Ingolf Bernhardt, Elisa Fermo |
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| Rok vydání: | 2021 |
| Předmět: |
Membrane potential
Mutation Erythrocytes medicine.diagnostic_test PIEZO1 Senicapoc Hematology Agatoxins medicine.disease medicine.disease_cause Stimulus Report Ion Channels Flow cytometry Red blood cell chemistry.chemical_compound medicine.anatomical_structure chemistry Channelopathy medicine Biophysics Calcium Humans Channelopathies Intracellular |
| Zdroj: | Blood advances Blood Adv |
| ISSN: | 2473-9537 2473-9529 |
| DOI: | 10.1182/bloodadvances.2020003823 |
| Popis: | In patients with Gárdos channelopathy (p.R352H), an increased concentration of intracellular Ca2+ was previously reported. This is a surprising finding because the Gárdos channel (KCa3.1) is a K+ channel. Here, we confirm the increased intracellular Ca2+ for patients with the KCa3.1 mutation p.S314P. Furthermore, we provide the concept of KCa3.1 activity resulting in a flickering of red blood cell (RBC) membranepotential, which activates the CaV2.1 channel allowing Ca2+ to enter the RBC. Activity of the nonselective cation channel Piezo1 modulates the aforementioned interplay in away that a closed Piezo1 is in favor of the KCa3.1-CaV2.1 interaction. In contrast, Piezo1 openings compromise the membrane potential flickering, thus limiting the activity of CaV2.1. With the compound NS309, we mimic a gain-of-function mutation of KCa3.1. Assessing the RBC Ca2+ response by Fluo-4–based flow cytometry and by measuring the membrane potential using the Macey-Bennekou-Egée method, we provide data that support the concept of the KCa3.1/CaV2.1/Piezo1 interplay as a partial explanation for an increased number of high Ca2+ RBCs. With the pharmacological inhibition of KCa3.1 (TRAM34 and Senicapoc), CaV2.1 (ω-agatoxin TK), and Piezo1 (GsMTx-4), we could project the NS309 behavior of healthy RBCs to the RBCs of Gárdos channelopathy patients. |
| Databáze: | OpenAIRE |
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