Summary: New discovery could provide new opportunities for the treatment of depression and addiction.
Source: National Center for Biological Sciences.
Information flow in cells relies on calcium as a key agent in several signalling pathways. Calcium dependent signalling is crucial in nearly every aspect of life – muscle movement, immune reactions, nerve function, light sensing and many such processes. In fact, one could consider any cellular function, and calcium signalling is probably involved in it in some way. Now, researchers from the National Centre for Biological Sciences (NCBS), Bangalore have discovered a new player in calcium signalling pathways – a protein named Septin 7 that functions as a ‘molecular brake’ to Orai activation.
As calcium ions cannot cross cell membranes freely, the rise and fall of calcium levels within a cell are controlled through a set of proteins that act as channels for calcium ions. One such protein is Orai, that forms pores or channels in cell membranes and allows calcium ions to move through them in a regulated fashion. Since these proteins can be likened to ‘gatekeepers’ of the calcium entryways into cells, they are named after the mythological Greek Orai, also known as Horae or the gatekeepers of heaven. Researchers Bipan Kumar Deb and Trayambak Pathak from Prof. Gaiti Hasan’s group at NCBS have discovered that another protein known as Septin 7 acts as a ‘guard’ of the Orai proteins by regulating their activity.
Previous work from this group had established the critical role of calcium signalling and Orai for maintaining dopamine levels in flight circuit neurons in fruit fly (Drosophila) brains. Using this system as a platform, Prof. Hasan’s team investigated and established the role of Septin 7 as a ‘molecular brake’ of Orai in the neurons of these flies. This means that when Septin 7 levels are decreased in a cell, calcium entry via Orai goes up, leading to higher calcium concentrations within cells. The discovery has been published as a paper in the journal Nature Communications.
The negative nature of Orai regulation by Septin 7 could be a therapeutically important one. “Most drugs work by inhibiting the function of a protein, and inhibiting most proteins causes the processes they are involved in to be reduced. In this case, inhibiting Septin 7 can actually raise intracellular calcium levels,” says Bipan Kumar Deb, the lead author of the paper.
“In the context of neural function, we know that under some conditions, reduced calcium signalling can lead to neurodegeneration. Rare genetic disorders such as spinocerebellar ataxias are thought to be caused by calcium signalling dysregulations. Future therapies for certain classes of such disorders could focus on Septin 7 as a therapeutic target,” adds Prof. Hasan.
The next challenge the team intends to address involves studying the role of Septin 7 in Orai regulation in mammalian cells. Future work also involves studying the role of Septin 7 in cells other than neuronal cells, specifically, in the cells of the immune system. “The Orai gene was first discovered in patients with Severe Combined Immuno-Deficency (SCID) syndrome, and subsequently an essential role for Orai proteins in immune cell function was uncovered,” says Deb. “Therefore, it is highly likely that Septin 7 also may play a role in calcium signalling mechanisms of the immune system, and we are already planning experiments to pursue this line of investigation,” he adds with enthusiasm.
About this neuroscience research article
Funding: Council of Scientific and Industrial Research, Government of India, National Centre for Biological Sciences, Tata Institute of Fundamental Research funded this study.
Source: Gaiti Hasan – National Center for Biological Sciences Image Source: This NeuroscienceNews.com image is credited to NCBS. Original Research: Full open access research for “Store-independent modulation of Ca2+ entry through Orai by Septin 7” by Bipan Kumar Deb, Trayambak Pathak and Gaiti Hasan in Nature Communications. Published online May 26 2016 doi:10.1038/ncomms11751
Cite This NeuroscienceNews.com Article
[cbtabs][cbtab title=”MLA”]National Center for Biological Sciences. “Guarding the Gatekeepers: New Player in Calcium Signalling Pathways Discovered.” NeuroscienceNews. NeuroscienceNews, 29 May 2016. <https://neurosciencenews.com/septin-7-calcium-signalling-4339/>.[/cbtab][cbtab title=”APA”]National Center for Biological Sciences. (2016, May 29). Guarding the Gatekeepers: New Player in Calcium Signalling Pathways Discovered. NeuroscienceNews. Retrieved May 29, 2016 from https://neurosciencenews.com/septin-7-calcium-signalling-4339/[/cbtab][cbtab title=”Chicago”]National Center for Biological Sciences. “Guarding the Gatekeepers: New Player in Calcium Signalling Pathways Discovered.” https://neurosciencenews.com/septin-7-calcium-signalling-4339/ (accessed May 29, 2016).[/cbtab][/cbtabs]
Store-independent modulation of Ca2+ entry through Orai by Septin 7
Orai channels are required for store-operated Ca2+ entry (SOCE) in multiple cell types. Septins are a class of GTP-binding proteins that function as diffusion barriers in cells. Here we show that Septin 7 acts as a ‘molecular brake’ on activation of Orai channels in Drosophila neurons. Lowering Septin 7 levels results in dOrai-mediated Ca2+ entry and higher cytosolic Ca2+ in resting neurons. This Ca2+ entry is independent of depletion of endoplasmic reticulum Ca2+ stores and Ca2+ release through the inositol-1,4,5-trisphosphate receptor. Importantly, store-independent Ca2+ entry through Orai compensates for reduced SOCE in the Drosophila flight circuit. Moreover, overexpression of Septin 7 reduces both SOCE and flight duration, supporting its role as a negative regulator of Orai channel function in vivo. Septin 7 levels in neurons can, therefore, alter neural circuit function by modulating Orai function and Ca2+ homeostasis.
“Store-independent modulation of Ca2+ entry through Orai by Septin 7” by Bipan Kumar Deb, Trayambak Pathak and Gaiti Hasan in Nature Communications. Published online May 26 2016 doi:10.1038/ncomms11751