Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we will assume that you are happy to receive all cookies and you will not see this message again. Click 'Find out more' for information on how to change your cookie settings.

Researchers in the Department of Physiology, Anatomy and Genetics publish in the prestigious Molecular Cell an article entitled "Distinct Spatial Ca2+ Signatures Selectively Activate Different NFAT Transcription Factor Isoforms"

Many proteins have multiple isoforms that are often co-expressed in the same cell. Examples include ion channels, metabolic enzymes, kinases and transcription factors that regulate gene expression. Isoforms can arise from different genes or through alternative splicing of the same gene. Protein isoforms are ubiquitous in nature. The fact that green algae, yeast, Caenorhabditis elegans and vertebrates all express several protein isoforms reinforces the view that this tight evolutionary conservation underlies important, isoform-specific biological function.

A critical question in cell biology is therefore how some isoforms can be activated and not others when several are co-expressed within the same cell. A partial answer has been provided by the finding that isoforms of protein kinases are corralled to different sub-cellular locations, controlling only those substrates constrained within the immediate vicinity. However, many protein isoforms share the same spatial domain and are activated by the same intracellular messenger. How can one isoform now be activated selectively and how might it gain access to targets that other isoforms are excluded from? This issue is nicely encapsulated by the NFAT family of transcription factors, which are essential for vertebrate development, differentiation and function. NFAT proteins share the same spatial and temporal domain and are activated by the same intracellular signal, a rise in cytoplasmic Ca2+. How can different NFAT proteins be selectively activated?

Professor Anant Parekh’s group in DPAG have directly addressed this question, comparing the closely related NFAT1 and NFAT4 isoforms. Their new findings, published in this month’s Molecular Cell (58, 232-243), demonstrate that NFAT1 has a private line of communication with plasma membrane calcium channels, activating in response to Ca2+ microdomains near the open channels. By contrast NFAT4 is more of a co-incidence detector, requiring both local Ca2+ entry through the same channels as well as a rise in nuclear Ca2+. These different Ca2+-dependencies enable agonist to recruit different isoform combinations as stimulus strength increases. The results identify a new mechanism that enables selective activation of closely related proteins within the same cell. “This is a novel mechanism that enables a physiological trigger to recruit different transcription factors in a manner determined by stimulus intensity”, said Dr Kar. Professor Parekh added: “Differential recruitment of subtly distinct signaling molecules increases the temporal bandwidth for information processing in a biological system”. Professor Gill and colleagues from Pennsylvania, USA, have written a commentary in Molecular Cell (58, 197-199) that accompanies the article.

More information on the Molecular Cell website

Similar stories

Oxford-led research maps milestone stage of human development for the first time

Scientists have shed light on an important stage of early embryonic development that has never been fully mapped out in humans before.

Mapping uncharted networks in the progression of Parkinson’s

A major new $9 million project funded by the Aligning Science Across Parkinson’s (ASAP) initiative will map the original circuits vulnerable to Parkinson’s on an unprecedented scale. The project is a collaboration between core investigators Stephanie Cragg, Richard Wade-Martins, and Peter Magill at Oxford, Mark Howe at Boston University and Dinos Meletis at the Karolinska Institutet, as well as collaborators Yulong Li at Peking University and Michael Lin at Stanford University.

Drug could help diabetic hearts recover after a heart attack

New research led by Associate Professor Lisa Heather has found that a drug known as molidustat, currently in clinical trials for another condition, could reduce risk of heart failure after heart attacks.

Blood bank storage can reduce ability of transfusions to treat anaemia

New research from the Swietach Group in collaboration with NHS Blood and Transplant has demonstrated that the process of storing blood in blood banks can negatively impact the function of red blood cells and consequently may reduce the effectiveness of blood transfusions, a treatment commonly used to combat anaemia.

Overlapping second messengers increase dynamic control of physiological responses

New research from the Parekh and Zaccolo groups reveals that a prototypical anchoring protein, known to be responsible for regulating several important physiological processes, also orchestrates the formation of two important universal second messengers.