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A new study by researchers at Saarland University and the University of Freiburg has now been published in Nature Communications.
The following text has been machine translated from the German with no human editing.
Whether it is the contraction of a muscle or signal transmission in the brain, all these processes are based on electrical signals in the nerve cells. They are triggered by the interaction of ions, among which calcium plays a key role: ‘When calcium enters the cell, it acts like a switch that turns a protein's function on or off,’ says Heiko Rieger, Professor of Theoretical Physics at Saarland University. When a signal is transmitted from one nerve cell to the next, for example, this is done by neurotransmitters that are released from small vesicles at the synapses. The vesicles fuse with the membrane of the synapse, and their contents pass through the synaptic cleft to the neighbouring nerve cell. ‘This process is triggered by calcium ions. They set in motion the machinery that pulls the vesicles to the membrane, opens them and releases the neurotransmitter,’ explains Rieger. It is crucial that the intracellular calcium concentration is then immediately lowered again to prepare the cell for the next signal transmission.
So how do the calcium ions get into the cell so quickly – and, above all, how do they get out again? Heiko Rieger explains that the enormous concentration gradient is responsible for the influx into the cell. "Since calcium concentrations outside the cell are much higher than inside the cell, calcium ions diffuse into the cell with the gradient. To do this, calcium channels open and around 100,000 calcium ions flow through each channel per second." As soon as the signal is over, they must be transported out of the cell as quickly as possible – against the concentration gradient. ‘Until now, it was assumed that either calcium buffers within the cell or pumps in the cell walls were responsible for this task – although it was believed that the pumps worked far too slowly and that the buffers were therefore more likely to be responsible for rapid disposal.’
In their new paper, scientists from Saarland University (Prof. Heiko Rieger, Prof. Dieter Bruns, Dr Yvonne Schwarz and Barbara Schmidt) and the University of Freiburg show that it is in fact the calcium pumps in the plasma membrane that are largely responsible for the rapid pumping of calcium ions out of the cell interior (using ATP, or adenosine triphosphate, as their energy source). What is remarkable about this discovery is that these so-called plasma membrane calcium ATPases (PMCA for short) do not operate at 100 hertz, i.e. 100 cycles per second, as was long believed, but in the high kilohertz range: This means that they pump 10,000 or more calcium ions out of the cell per second and thus work more than 100 times faster than previously assumed. This enables them to regulate calcium concentrations inside the cell precisely and quickly,’ explains Heiko Rieger. This finding refutes previous scientific assumptions and is the result of pioneering work by colleagues in Freiburg: ’They were the first to succeed in measuring the work of PMCA in a fully functional state."
The PMCA pumps interact with the membrane lipid PtdIns(4,5)P2. The resulting PMCA2-neuroplastin complexes enable, among other things, the rapid binding and release of calcium ions, thus enabling exceptionally high pumping performance. Without this lipid binding, transport slows down significantly.
For its functional experiments, the Freiburg team used ultra-fast sensors (calcium-activated potassium channels) that make changes in calcium concentration visible in the millisecond range. Together with the densities of the pump complexes in the cell membranes (around 55 complexes per square micrometre) determined by electron microscopy, the researchers were able to reliably calculate the transport speed of the PMCA pumps for the first time using a mathematical model developed by Professor Heiko Rieger.
The insights gained into the crucial functional mechanisms of ultra-fast calcium pumps open up new perspectives for understanding neuronal diseases. A variety of neurodegenerative diseases, such as Alzheimer's disease, cardiovascular disease and diabetes, are associated with disturbances in intracellular calcium levels. In this respect, the research results could create new targets for active substances that specifically intervene in calcium-regulated signalling pathways.
Original publication:
Cristina E. Constantin, Barbara Schmidt, Yvonne Schwarz, Harumi Harada, Astrid Kollewe, Catrin S. Müller, Sebastian Henrich, Botond Gaal, Akos Kulik, Dieter Bruns, Uwe Schulte, Heiko Rieger & Bernd Fakler: Ca2+-pumping by PMCA-neuroplastin complexes operates in the kiloHertz-range. Nature Communications 16, 7550 (2025)
https://doi.org/10.1038/s41467-025-62735-5
Questions:
Professor Dr. Heiko Rieger
Universität des Saarlandes
Professur für Theoretische Physik, Arbeitsgruppe für theoretische Biophysik, statistische Physik und Computerphysik
Tel.: +49 681 302-3969 (Sekretariat: 302-2423)
E-Mail: heiko.rieger@uni-saarland.de
https://www.rieger.uni-saarland.de/
