The Function of Ion Channels and Membrane Potential in Red Blood Cells: Toward a Systematic Analysis of the Erythroid Channelome

Abstract

Erythrocytes represent at least 60% of all cells in the human body. During circulation, they experience a huge variety of physical and chemical stimulations, such as pressure, shear stress, hormones or osmolarity changes. These signals are translated into cellular responses through ion channels that modulate erythrocyte function. Ion channels in erythrocytes are only recently recognized as utmost important players in physiology and pathophysiology. Despite this awareness, their signaling, interactions and concerted regulation, such as the generation and effects of “pseudo action potentials”, remain elusive. We propose a systematic, conjoined approach using molecular biology, in vitro erythropoiesis, state-of-the-art electrophysiological techniques, and channelopathy patient samples to decipher the role of ion channel functions in health and disease. We need to overcome challenges such as the heterogeneity of the cell population (120 days lifespan without protein renewal) or the access to large cohorts of patients. Thereto we will use genetic manipulation of progenitors, cell differentiation into erythrocytes, and statistically efficient electrophysiological recordings of ion channel activity.

Evidence of in vivo exogen protein uptake by red blood cells: a putative therapeutic concept

“…The molecular signaling capacity of red blood cells (RBCs) is increasingly recognized [1][2][3] as is their functional heterogeneity. 4,5 In this context, ion channels are also slowly being acknowledged as physiologically relevant signal mediators in RBCs 6,7 although their copy number per cell is very low. [8][9][10] The presence of transient receptor potential channel of canonical type, member 6 (TRPC6) has been indicated in the protein level in mature RBCs, 11 but this finding was controversially discussed.…”

Unidirectional fluxes of monovalent ions in human erythrocytes compared with lymphoid U937 cells: Transient processes after stopping the sodium pump and in response to osmotic challenge

“…Most likely, Gardos channels, as well as the recently discovered mechanosensitive cationic PIEZO1 channels, which are inactive at rest, play the significant effecter and regulatory role, participating in specific physiological reactions of erythrocytes, for example, when passing through the capillary network [ 2 , 47 ]. Furthermore, the activity of the channels can change considerably under various pathological conditions [ 26 , 28 , 40 , 46 , 48 ].…”

Physical Properties of Blood and their Relationship to Clinical Conditions

“…As detailed above, RBC deformability is highly dependent on a normal cellular surface-to-volume ratio. The internal volume of individual erythrocytes is tightly regulated by ion channels ( von Lindern et al, 2022 ) and any change in the activity of these, such as in channelopathies, may have detrimental consequences. Hereditary xerocytosis (i.e., dehydrated stomatocytosis) is often cited as an example and is caused by a gain-of-function mutation in PIEZ O 1 ( von Lindern et al, 2022 ; Picard et al, 2019 ).…”

“…The internal volume of individual erythrocytes is tightly regulated by ion channels ( von Lindern et al, 2022 ) and any change in the activity of these, such as in channelopathies, may have detrimental consequences. Hereditary xerocytosis (i.e., dehydrated stomatocytosis) is often cited as an example and is caused by a gain-of-function mutation in PIEZ O 1 ( von Lindern et al, 2022 ; Picard et al, 2019 ). Associated clinical consequences include anemia, hemolysis, and iron overload ( Picard et al, 2019 ).…”