Vm-related extracellular potentials observed in red blood cells

Abstract

Even in nonexcitable cells, the membrane potential Vm is fundamental to cell function, with roles from ion channel regulation, development, to cancer metastasis. Vm arises from transmembrane ion concentration gradients; standard models assume homogeneous extracellular and intracellular ion concentrations, and that Vm only exists across the cell membrane and has no significance beyond it. Using red blood cells, we show that this is incorrect, or at least incomplete; Vm is detectable beyond the cell surface, and modulating Vm produces quantifiable and consistent changes in extracellular potential. Evidence strongly suggests this is due to capacitive coupling between Vm and the electrical double layer, rather than molecular transporters. We show that modulating Vm changes the extracellular ion composition, mimicking the behaviour if voltage-gated ion channels in non-excitable channels. We also observed Vm-synchronised circadian rhythms in extracellular potential, with significant implications for cell–cell interactions and cardiovascular disease.

Cytoplasmic anion/cation imbalances applied across the membrane capacitance may form a significant component of the resting membrane potential of red blood cells

“…A best-fit value for Ψ st,o of − 31 mV was previously obtained in control solutions 11 ; values under the other conditions described here are available in that work. If we assume that there is ion diffusion across the membrane, then alteration of these ion concentrations will determine the extent of transmembrane diffusion; if cytoplasmic ions equilibrate with the medium, then this expression would represent the ionic strengths across which the cytoplasm would equilibrate.…”

“…This yields the expression: where 1/κ is the Debye length; the number of ions per m 3 for a medium conductivity of 1 S m −1 , and A as defined in Eq. (11). V x was as before.…”

“…For example, Tyner et al 10 used “nanosized voltmeter” nanoparticles to map the intracellular influence of V m and observed “E fields extending out much farther (microns) into the cytosol”. Furthermore, recent observations of red blood cells (RBCs) have indicated that the extracellular ζ -potential (a voltage field that arises from a cell surface charge and extends several nanometres from the cell surface) is affected by V m , via a process related to the capacitance of the electrical double-layer 11 . Similar phenomena have also been identified in platelets 12 .…”

Circadian rhythmicity in murine blood: Electrical effects of malaria infection and anemia

“…DEP has revealed circadian cycles in the electrical properties of RBCs ( Henslee et al, 2017 ; Beale et al, 2019 ; Beale et al, 2022 ) human as well as sub-2 h, ultradian rhythms in the RBCs of voles ( Hoettges et al, 2019 ). More recently, connections have been demonstrated between these DEP-derived electrical parameters and other electrical measures of cell function, such as the membrane potential (V m ) and the extracellular electrical potential (the ζ-potential) that regulates the way cells interact with other cells and biological entities in their immediate environment ( Hughes et al, 2021 ; Hughes et al, 2022 ).…”

On-Chip Single-Cell Bioelectrical Analysis for Identification of Cell Electrical Phenotyping in Response to Sequential Electric Signal Modulation

“…The dielectric properties of a living cell membrane inside a microfluidic device are indicators of their physiological status, which is closely connected with cell state and function. Several previous studies have shown that changes in these dielectric properties are linked to processes such as ion channel activation [ 1 , 2 ]; membrane fusion; and budding and flip-flop [ 3 , 4 ], which contribute to the characterization of cell circadian rhythm [ 1 , 5 ]; cell progression [ 6 , 7 ]; cell viability [ 8 , 9 , 10 ]; and cell malignancy [ 11 , 12 ]. Recent advances in microfluidic and micro/nanotechnology have enabled the detection of cell membrane dielectric response at a whole-cell level, which makes it an attractive label-free biomarker candidate for discriminating cell populations for stem cell differentiation [ 13 , 14 ], leukocyte activation [ 15 ], and circulating tumor cell existence [ 16 ].…”