Indicator molecules make changes in calcium levels outside of cells visible for the first time
The mineral calcium is a crucial building block of countless body functions. For many processes, calcium flows selectively from the cells’ surroundings into them. However, the behavior of calcium concentrations in the important extracellular area has hardly been studied so far due to a lack of methods. Now, after years of development, a team led by Oliver Griesbeck of the Max Planck Institute for Biological Intelligence is providing sensors that close this gap.
Calcium is important for bones, teeth and muscles. Yet, calcium also plays a crucial role in the nervous system: If, for example, an impulse is to be passed on from one nerve cell to the next, voltage-dependent calcium channels open and the mineral compound flows into the nerve cell from the nearby environment. In response to this increase in calcium, the cell releases so-called neurotransmitter molecules that can activate a downstream neuron. In this way, a message can be transmitted from one cell to the next.
What calcium does inside a cell has been quite well investigated. The calcium occurrence outside the cells, on the other hand, was mostly noted as “present” and then largely ignored. This was not least due to the fact that – especially in the brain – the interstitial spaces between cells are often very narrow, widely branched, and sometimes partially divided into individual subspaces. Together with the fact that there were hardly any suitable tools for detecting calcium outside cells, detailed investigations were almost impossible.
“For a comprehensive understanding of calcium functions in the body, it is important to be able to study the interplay of calcium deposits both inside and outside cells directly in the tissue. We therefore developed genetically encoded biosensors that can be used to measure calcium in the often difficult-to-access intercellular spaces,” relates Oliver Griesbeck, head of a research group at the Max Planck Institute for Biological Intelligence.
What sounds almost simple when told by Oliver Griesbeck is the result of years of work. Time and again, he and his colleagues had to optimize the newly developed sensors to meet all the requirements. After all, the sensors not only have to work reliably at the much higher calcium concentrations outside cells; they also have to be sensitive enough to indicate a change in concentration here with a large fluorescence change. This is exactly what the team has now achieved with the new GreenT-EC biosensors.
The newly developed GreenT-EC biomolecules are produced by a genetically modified organism itself. If the molecules are transported to the extracellular space, the sensors fluoresce bright green due to the high calcium concentration in this environment. A change in concentration here is then indicated by measurable changes in fluorescence.
“It was quite impressive when we were finally able to really observe the dynamics of calcium concentrations outside cells,” recalls Oliver Griesbeck. The team has already tested the new sensors in various animal species, where they worked reliably. “Now we hope that the sensors will be used in a wide variety of studies, providing answers to the many unanswered questions about the movement of calcium in the body.”
Ariel A. Valiente-Gabioud, Inés Garteizgogeascoa Suñer, Agata Idziak, Arne Fabritius, Jérome Basquin, Julie Angibaud, U. Valentin Nägerl, Sumeet Pal Singh, Oliver Griesbeck; Fluorescent Sensors for Imaging of Interstitial Calcium; Nature Communications, online 5. Oct. 2023. Link.