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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.

Decorative comparison of rest cells and simulated cells
Proximity ligation assay reveals close interaction between AKAP79 and Orai1 Ca2+ channels, as seen by an increase in the number of small spots (in red). Red spots arise from tight co-localisation between the two proteins.

Increased biological complexity is accompanied by augmented spatial and temporal organization of biochemical processes. In many fundamental metabolic pathways, enzymes are not spatially segregated in the cytoplasm but physically interact to form functional multi-enzyme complexes in which the products of one reaction are readily accessible to the next enzyme in the cascade. Scaffolding proteins, such as members of the A kinase anchoring proteins (AKAPs) also provide a conserved and effective means for constraining enzymes and signalling molecules close to their respective targets. AKAP79 is the prototypical AKAP and regulates important physiological processes including long-term synaptic depression, insulin secretion and activation of the Ca2+-dependent transcription factor NFAT.

A collaborative study from the Parekh and Zaccolo groups have now discovered that AKAP79 orchestrates the formation of two ancient and highly conserved signal transduction pathways in the same sub-cellular region. Cytosolic Ca2+ and cyclic AMP (cAMP) are two universal second messengers which are recruited by many hormones and neurotransmitters to activate cellular effects. Both messengers elicit responses by binding to proteins; cAMP binds to and activates protein kinase A, which then phosphorylates a range of targets. Ca2+ can bind to multiple proteins including the protein phosphatase calcineurin, which dephosphorylates proteins. A major target of calcineurin is the transcription factor NFAT, which drives expression of numerous pro-inflammatory genes.

In a new paper, first authored by Dr Pulak Kar, the team demonstrate that protein kinase A, calcineurin and NFAT are bound to AKAP79 in the inner leaflet of the plasma membrane but this signalling complex relocates adjacent to a Ca2+ channel after cell stimulation. The authors also find that phosphodiesterase 4 (PDE4), an enzyme that rapidly degrades cAMP, is also part of the AKAP79 signalosome and associates with AKAP79 in a manner dependent on protein kinase A. The new results reveal that two ancient signalling pathways, Ca2+-calcineurin and cAMP-protein kinase A, are assembled close to Ca2+ channels and in a manner wholly dependent on the presence of AKAP79. These discoveries show how AKAP79 helps ensure Ca2+ and cAMP remain local signals, confined to sub-cellular regions, and further reveal new sites for interaction between these universal signalling pathways.

The full paper, "AKAP79 orchestrates a cyclic AMP signalosome adjacent to Orai1 Ca2+ channels" is available to read in Function.

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REF 2021 results