Mechanistic ion channel interactions in red cells of patients with Gárdos channelopathy

Blood Advances - Tập 5 - Trang 3303-3308 - 2021
Julia Jansen1,2, Min Qiao1,2, Laura Hertz1,2, Xijia Wang3, Elisa Fermo4, Anna Zaninoni4, Raffaella Colombatti5, Ingolf Bernhardt3, Paola Bianchi4, Lars Kaestner1,2
1Theoretical Medicine and Biosciences, Saarland University, Homburg, Germany
2Experimental Physics
3Laboratory of Biophysics, Saarland University, Saarbruecken, Germany
4Unità Operativa Semplice (UOS) Fisiopatologia delle Anemie, Unità Operativa Complessa (UOC) Ematologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
5Clinic of Pediatric Hematology-Oncology, Department of Woman's and Child's Health, University of Padua, Padua, Italy

Tóm tắt

Abstract 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.

Tài liệu tham khảo

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Blood Advances

Tập 5

3303-3308

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