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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.

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