Cell Transport Carriers Traverse Hostile Territory
Hardly a month goes by
without new research revealing
another wonder in cells.
by Jerry Bergman, PhD
One question that has perplexed cell biologists for decades is,“How do the cell transport carriers survive the hostile environment as they travel from one cell to their destination in another cell?” Intercellular travel requires navigating through the different biological environments in cells, blood vessels, and bodily fluids.
One hazard is pH (acid-base) differences. Intracellular pH (the pH level inside a cell) is approximately 7.0, or neutral between acidic and basic. This is different than the pH of extracellular fluid. The pH differences are a result of electrolyte ionic variations caused chiefly by sodium (Na+), potassium (K+), magnesium (Mg2+), calcium (Ca2+), phosphate (HPO42-), chloride (Cl–), and bicarbonate (HCO3-) ion concentrations.
The greater the concentration of hydrogen ions, the more acidic the medium. Water is the most abundant molecule in cells, accounting for over 70 percent of total cell mass. Although inorganic ions in the cell constitute less than one percent of the cell mass, they serve critical roles in cell function. For this reason, the interactions between water and the other cell constituents are of central importance in biological chemistry.[1]
Classification of extracellular vesicles (EVs) according to size. Exosomes (30-150 nm), microvesicles (100-1000 nm), and apoptotic bodies (800-5000 nm). From Wikimedia commons.
Channels and Vesicles
It has been well-known that ion channels are critical to maintain any structure that is surrounded by a membrane. These extracellular membrane-bound vesicles contain cargo that can either protect or harm the body cells. A paper in Nature Communications by Sanghvi, Singh and colleagues describes how vesicles play an important role in intercellular communications, immune responses, viral pathogenicity, cardiovascular diseases, neurological disorders, and cancer progression.[2]
Extracellular vesicle systems are required to safely transport molecules from the cellular interior to the extracellular environment, and then back into another cell type. Several known reasons include the following:
Extracellular vesicles carry proteins and other molecules from donor to recipient cells to alter physiological and biological responses. In addition to facilitating cellular communication and maintaining cellular balance, the particles have been linked to immune responses, viral infectiousness, and cardiovascular disease, cancer and neurological disorders.[3]
Without this complex extracellular vesicle system, cell biology interactions could not exist, nor could life.[4]
Structure and Function of Vesicles
These vesicles contain an ion channel consisting of a protein that opens, allowing electrical charges to pass through the protective outer membrane.[5] The Singh et al. study was the first to document how these microscopic extracellular vesicles stay intact in their journeys.
The Singh et al. research demonstrated that these extracellular vesicles require the use of protein ion channels to prevent the extracellular vesicle membranes from bursting due to water movement triggered by osmosis. The ion channel is a protein structure that opens a corridor which allows electrical charges to pass through the protective outer membrane, a necessary step to keep contents and conditions stable inside.
One example is the electrolyte potassium, the most abundant positively charged ion inside of cells. In the extracellular environment, potassium concentration is 30-fold lower than it is inside. Consequently, when an extracellular vesicle travels from a high potassium concentration to a low potassium concentration, the protein ion channels allow the movement toward the ion equilibrium.
A major problem in discovering these extracellular vesicle structures is that they are extremely small (from 30 to 60 nm). To empirically document that they exist, Singh et al. pioneered a technique called near-field electrophysiology to record the low currents in the extracellular vesicles’ membranes. This method established the presence of a calcium-activated, large-conductance potassium channel.
Examples of the many extracellular vesicles (the small blue round structures). From Liu, Shan, et al., “Extracellular vesicles: Emerging tools as therapeutic agent carriers,” Acta Pharmaceutica Sinica B 12(10):3822-3842, 11 May 2022.
Summary
A possible evolutionary explanation for the origin of these extracellular vesicles was never mentioned in the Nature Communications report, nor in other published reviews of their research. The research in this area is new and much yet needs to be learned, but as far as is currently known all multicellular organisms require it to communicate between cells. The researchers are still working to identify the specific proteins called transporters that enable vesicles to maintain their required ionic balance as they move from the extracellular environment back into a cell with different ionic concentrations. From what is presently known, without this extracellular vesicle system protein, multicellular organisms would be unable to survive. It is one more example of the many complex structures that are required for life.
References
[1] Cooper, G.M. The Cell: A Molecular Approach, Chapter 2: “The Molecular Composition of Cells,” Sinauer Associates, Sunderland, MA, 2000.
[2] Sanghvi, Shridhar, et al., “Functional large-conductance calcium and voltage-gated potassium channels in extracellular vesicles act as gatekeepers of structural and functional integrity, Nature Communications16(1), DOI: 10.1038/s41467-024-55379-4, 2025.
[3] Ohio State University, “The proteins that make cell-to-cell cargo transport possible,” Science Daily, 15 January 2025.
[4] Ohio State University, 2025.
[5] Caldwell, E., “The proteins that make cell-to-cell cargo transport possible,” Ohio State University News, 15 January 2025.