Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

A new study from the Parekh Group has resolved a long-standing question in our understanding of intracellular Ca2+ signalling, namely how a specific type of Ca2+ channel is uniquely able to signal to the nucleus to regulate gene expression. By unravelling this mechanism, researchers have identified a new approach for developing immunosuppressant drugs.

Upper panel: Rest
Lower panel: stimulated

Images from left:
Orai1-GFP
STIM1-YFP
DAPI (nuclear stain)
NFAT-cherry
All merged
From left: Orai1, STIM1, DAPI, NFAT, All merged. Upper Panel: Rest. Lower Panel: Stimulated

Cytosolic Ca2+ is a universal cellular signal which activates a broad range of responses from exocytosis and muscle contraction to energy production and cell growth and differentiation. Too much Ca2+ can cause cell death, through either apoptosis or necrosis. How a cell responds to a Ca2+ signal can therefore be a matter of life and death.  

To avoid conflicting and harmful outcomes, eukaryotic cells often confine the Ca2+ signal to spatially restricted sub-compartments. The smallest signalling unit is the Ca2+ nanodomain, which forms when Ca2+ channels open. Ca2+nanodomains near voltage-gated Ca2+ channels drive neurotransmitter release or cause a heart beat. In immune cells, Ca2+ entry through store-operated Orai Ca2+ channels activates NFAT transcription factors, which in turn increase expression of chemokines and cytokines that orchestrate inflammatory responses. NFAT is activated following dephosphorylation by the Ca2+-activated protein phosphatase calcineurin, the target for immunosuppressant drugs that enable successful organ transplantation. Previous work from the Parekh group had demonstrated that the Orai1 was able to activate gene expression whereas Ca2+ entry through either other Orai homologues or different Ca2+ channels was ineffective. Orai1 has a private line of communication with the nucleus, but the molecular basis for this privileged route is unknown. 

In a new paper, first authored by Dr Pulak Kar, Parekh Group researchers have discovered how Orai1 channels are uniquely able to control gene expression. They identify a region on the N terminus of Orai1 that is indispensable for stimulating gene expression. This region binds to the scaffolding protein AKAP79, which binds both calcineurin and NFAT, and therefore places the enzyme and transcription factor next to the Ca2+ channel. The region, called AKAP79 Association Region (AKAR), is unique to Orai1, being absent in Orai homologues and other Ca2+ channels.  This close physical interaction ensures that only Ca2+flux through Orai1 is able to stimulate gene expression. 

Kar et al go on to show that a peptide mimicking AKAR uncouples Orai1 from AKAP79 and suppresses cytokine production, leaving other functional consequences of the channel intact. In collaboration with Dr Nader Amin in Chemistry, the authors present an NMR structure of the peptide. Strikingly, it has a small pocket that is made of a series of proline residues. Mutation of the prolines abolished the inhibitory effects of the peptide, showing that the pocket was required for function. Whilst current immunosuppressants used in the clinic, such as cyclosporinA and tacrolimus, have revolutionized transplant surgery, they raise blood pressure and cause irreversible glomerular nephrotoxicity, which can lead to death. Targeting the Orai1-AKAP79 interaction with drugs that occupy the pocket region opens up the possibility for developing new immunosuppressants that do not affect blood pressure or compromise renal function.  

The full paper, "The N terminus of Orai1 couples to the AKAP79 signaling complex to drive NFAT1 activation by local Ca 2+ entry" is available to read in PNAS.

Similar stories

New blood test from DPAG cardiac researchers could save lives of heart attack victims

Researchers from the Herring group have developed a blood test that measures stress hormone levels after heart attacks. The test – costing just £10 – could ensure patients receive timely life-saving treatment.

Mootaz Salman set to target new treatments for stroke

The Chief Scientist Office of the Government of Scotland has awarded a collaborative grant of £298,966 to Dr Mootaz Salman to seek new therapeutic avenues to treat stroke.

New BBSRC grant to further our insights into how the cortex controls sleep

Professor of Sleep Physiology Vladyslav Vyazovskiy and Professor of Developmental Neuroscience Zoltán Molnár have been awarded a Project Grant from the Biotechnology and Biological Sciences Research Council (BBSRC) for “Brain mechanisms of sleep: top-down or bottom-up?”

Raised intracellular chloride levels underlie the effects of tiredness in cortex

A new study, co-authored by Professor Vladyslav Vyazovskiy, published in Nature Neuroscience, has revealed that intracellular chloride levels within cortical pyramidal neurons reflect sleep–wake history.

Key cause of type 2 diabetes uncovered

Research led by Dr Elizabeth Haythorne and Professor Frances Ashcroft reveals high blood glucose reprograms the metabolism of pancreatic beta-cells in diabetes. They have discovered that glucose metabolites, rather than glucose itself, are key to the progression of type 2 diabetes. Glucose metabolites damage pancreatic beta-cell function, so they are unable to release enough of the hormone insulin. Reducing the rate at which glucose is metabolised, and these glucose metabolites build up, can prevent the effects of hyperglycaemia.