Calcium ‘communicates’ and can sense declining cell health leading to neurological conditions
In a first, a group of neurobiologists from the National Centre for Biological Sciences (NCBS-TIFR) have identified a key protein, whose dysfunction could potentially trigger neurodegenerative diseases.
Using the Drosophila model, the group led by Professor Raghu Padinjat has identified a protein named Extended synaptotagmin (Esyt) that sits close to the cell membrane. The study was published in the Journal of Cell Biology.
A cell’s exterior region comprises plasma membrane(PM) and endoplasmic reticulum (ER). PM forms the cell’s outer boundary, gatekeeping entry of material into the cell and communicating between the outside of the cell and its interior, whereas the ER is a network of membranes inside the cell. The region where PM and ER meet is known as the membrane contact site (MCS). This site permits intra-cellular signalling, transporting essentials like lipids and calcium between organelles.
Over the past decade or so, modern genomics and technological advancements have helped scientists establish that more than 20 proteins are located at the MCS between the ER and PM. However, there is still limited scientific evidence to answer why certain proteins are prevalent at these sites or what role they play in cell health.
The present study has tracked how some of these proteins tune the operations at the cell MCS, whose health is directly linked to cell health.
What we know
Past research from Padinjat’s lab has shown that a protein, Retinal Degeneration B (RDGB), present at MCS is essential for lipid transfer across the membranes. The absence of these protein can make the flies go blind. It was known that MCS density changes in response to illumination. But how is this controlled?
What is calcium’s role?
For photoreceptors, special type of neurons in the retina, calcium is a message encoder. It encodes and delivers information (about light intensity) from the surroundings to the cell, which in this case is the amount of light. When light is absorbed, the lipid transfer activity of RDGB at MCS is triggered. As lipids are exhausted, this stock needs to be replenished.
Confocal microscopy image depicting the localization of the calcium-binding mutant of dEsyt in Drosophila photoreceptors, along side the contact site marker RDGB and phalloidin labeling F-actin
“It will happen only when calcium is effectively able to communicate this to the cell. This means that the cell needs to stay informed about its surroundings, which we think is being done by the changes in intracellular calcium,” said Raghu Padinjat, Professor, NCBS.
Taking this research a step ahead with the newly identified protein Esyt, researchers said that it possesses a C2 domain that can bind and detect calcium. Loss of the ability to bind calcium by the C2 domain of Esyt makes the cell incapable of adjusting its MCS function in response to illumination.
“We hence propose that it is the Esyt’s strategic presence at the contact site that it can first decode the calcium binding to the C2 domain. To this, a cell then responds by either increasing or decreasing the number of contact sites for lipid transfers,” said Padinjat.
The presence of calcium is, therefore, a signal to the cells for undertaking enhanced amounts of lipid transfers and the need for creating more sites, ensuring smooth and continuous lipid transfer.
“We have established that it is this presence of calcium that governs lipid transfers into the cell,” he said.
For the first time, cell health has been closely tied to the presence of healthy contact sites.
“When the cell is unable to maintain healthy contact sites in adequate numbers, it could lead to neurodegenerative diseases, he said. “In Drosophila flies, they suffered retinal degeneration. The contact sites first disappear, after which the cell’s health is affected”. Calcium levels could be used smartly as sensors to track cell health and be able to detect onset of neurodegeneration, if any, the researchers noted.