INNOVATION – Ion Channels in Red Blood Cells

History

The 2021 Nobel Prize in Physiology or Medicine was awarded, in part, for the discovery of mechanosensitive PIEZO channels. We have already characterized PIEZO1 function in red blood cells before its molecular identity was established 1,2. We investigate the interplay of ion channels in erythrocytes and have introduced the concept of the pseudo-action potential (PAP)3. Our research has further elucidated the role of ion channels in rare erythrocyte disorders, leading to the recognition of Gardos channelopathy as a distinct clinical entity that differs from classical dehydrated stomatocytosis4. In addition, we were the first to employ automated patch-clamp technology to functionally validate a novel genetic variant associated with hereditary xerocytosis5.

1. Kaestner L, Christophersen P, Bernhardt I, Bennekou P. The non-selective voltage-activated cation channel in the human red blood cell membrane: reconciliation between two conflicting reports and further characterisation. Bioelectrochemistry 2000;52(2): 117–25.
2. Kaestner L, Egée S. Commentary: Voltage Gating of Mechanosensitive PIEZO Channels. Frontiers in Physiology 2018; 9:1565.
3. Jansen J, Qiao M, Hertz L, et al. Mechanistic ion channel interactions in red cells of patients with Gárdos channelopathy. Blood Adv 2021; 5(17): 3303–8.
4. Fermo E, Bogdanova A, Petkova-Kirova P, et al. “Gardos Channelopathy”: a variant of hereditary Stomatocytosis with complex molecular regulation. Scientific reports [Internet] 2017;7(1):1744.
5. Rotordam MG, Fermo E, Becker N, et al. A novel gain-of-function mutation of Piezo1 is functionally affirmed in red blood cells by high-throughput patch clamp. Haematologica 2019; 104(5): e179–83.

 

Current Work

During their circulation, red blood cells are exposed to a wide range of physical and chemical stimuli, including pressure, shear stress, hormones, and changes in osmolarity. These signals are sensed and translated into cellular responses by ion channels that regulate red blood cell function and homeostasis. Our research combines molecular biology, in vitro erythropoiesis, state-of-the-art electrophysiology, advanced functional analyses of red blood cells, and patient-derived samples from channelopathies and other red blood cell disorders to systematically decipher ion channel function and exploit this knowledge for the development of novel therapeutic strategies.

To overcome the longstanding challenges that have limited progress in the field, we employ genetic manipulation of erythroid progenitor cells followed by differentiation into red blood cells, enabling the direct investigation of specific channel variants and signaling pathways. In parallel, we use statistically robust, high-throughput electrophysiological approaches to address the intrinsic heterogeneity of circulating red blood cells, which arise from their 120-day lifespan and lack of protein renewal. Combined with access to well-characterized patient cohorts, this integrated experimental platform allows us to bridge fundamental ion channel biology with clinically relevant disease mechanisms and translational applications.

Funding: Doctoral Network INNOVATION, a Marie Skłodowska-Curie Action

Project Website