BKCa channels identified as essential regulators of extracellular vesicle integrity

/ in E-News

Scientists have discovered how extracellular vesicles maintain their structural integrity during cellular transport through blood vessels and bodily fluids, revealing a critical role for specialised ion channels that regulate internal conditions.

Researchers at The Ohio State University have uncovered the secret behind how tiny cell-derived particles called extracellular vesicles (EVs) maintain their structural integrity as they journey through the body’s fluids. Their study, published in Nature Communications on 2 January 2025, reveals that specific ion channels in the vesicle membranes help regulate internal conditions despite varying external environments.

The research team identified a calcium-activated large-conductance potassium channel (BKCa) that acts as a gatekeeper, allowing the vesicles to adapt to dramatic changes in ion concentrations as they move between cellular and extracellular environments.

“We have not only discovered ion channels in these vesicles. We have recorded functional ion channels for the first time ever,” said Harpreet Singh, professor of physiology and cell biology at Ohio State’s College of Medicine and co-lead author of the study.

Mechanism of action

The researchers demonstrated that these channels help EVs cope with substantial differences in potassium concentrations – up to 30-fold – between cellular interiors and the extracellular environment. Without this regulation, the vesicles would be subject to osmotic stress that could cause their membranes to burst.

Using a novel technique called near-field electrophysiology, the team recorded electrical currents across EV membranes, providing direct evidence of functional ion channels. They estimated approximately two functional channels per vesicle, which help maintain appropriate internal conditions.

Impact on cargo delivery

The study also revealed that these ion channels influence what cargo the vesicles can carry. When comparing vesicles from normal mice versus those lacking the BK channel gene, the researchers found significant differences in their RNA cargo, particularly molecules known to protect heart tissue.

“EVs present a wide heterogeneity in their sizes and content.

The precise mechanism of EVs heterogeneity is not yet elucidated. However, biogenesis in the originating cell and the downstream target cell are some of the key predictors of the variability in EVs,” the authors noted in their discussion.

Therapeutic implications

The findings have important implications for the therapeutic use of EVs, which are being investigated as potential drug delivery vehicles. The research showed that vesicles containing functional BK channels were better able to protect heart tissue from damage in mouse models of heart attack.

“People talk about loading these vesicles with charged molecules – whether it’s a drug, RNA proteins, or something else. If you’re loading them with charged molecules and you’re not managing ion homeostasis, you will have some sort of consequences,” Singh explained.

The researchers suggest their discovery could help improve the design of EV-based therapies by ensuring the right combination of ion channels and transporters are present to maintain vesicle stability during drug delivery.

The authors note that while this study focused on potassium channels, EVs likely contain other types of ion channels and transporters that warrant investigation. Understanding these mechanisms could lead to better therapeutic applications.

“Our discovery of functional BKCa channels in EVs highlights the diversity of these nanovesicles that are actively secreted by different cell types. This finding encourages further exploration of the roles that various ion channels and transporters play in EVs,” the authors concluded.

Reference:
Sanghvi, S., Sridharan, D., Evans, P., et. al. (2025). Functional large-conductance calcium and voltage-gated potassium channels in extracellular vesicles act as gatekeepers of structural and functional integrity. Nature Communications, 16(42). https://doi.org/10.1038/s41467-024-55379-4