AKAP79 Orchestrates a Cyclic AMP Signalosome Adjacent to Orai1 Ca2+ Channels.

To ensure specificity of response, eukaryotic cells often restrict signalling molecules to sub-cellular regions. The Ca2+ nanodomain is a spatially confined signal that arises near open Ca2+ channels. Ca2+ nanodomains near store-operated Orai1 channels stimulate the protein phosphatase calcineurin, which activates the transcription factor NFAT1, and both enzyme and target are initially attached to the plasma membrane through the scaffolding protein AKAP79. Here, we show that a cAMP signalling nexus also forms adjacent to Orai1. Protein kinase A and phosphodiesterase 4, an enzyme that rapidly breaks down cAMP, both associate with AKAP79 and realign close to Orai1 after stimulation. PCR and mass spectrometry failed to show expression of Ca2+-activated adenylyl cyclase 8 in HEK293 cells, whereas the enzyme was observed in neuronal cell lines. FRET and biochemical measurements of bulk cAMP and protein kinase A activity consistently failed to show an increase in adenylyl cyclase activity following even a large rise in cytosolic Ca2+. Furthermore, expression of AKAP79-CUTie, a cAMP FRET sensor tethered to AKAP79, did not report a rise in cAMP after stimulation, despite AKAP79 association with Orai1. Hence, HEK293 cells do not express functional active Ca2+-activated adenylyl cyclases including adenylyl cyclase 8. Our results show that two ancient second messengers are independently generated in nanodomains close to Orai1 Ca2+ channels.

The Role of Lipid Biomarkers in Major Depression.

In the UK, the lifetime-documented prevalence of major depressive disorder (MDD) is currently 10%. Despite its increasing prevalence and devastating impact on quality of life, the pathophysiological mechanisms underpinning MDD remain to be fully elucidated. Current theories of neurobiological components remain incomplete and protein-centric, rendering pharmacological treatment options suboptimal. In this review, we highlight the pivotal role of lipids in intra- and inter-neuronal functioning, emphasising the potential use of lipids as biomarkers for MDD. The latter has significant implications for improving our understanding of MDD at the cellular and circuit level. There is particular focus on cholesterol (high and low density lipoprotein), omega-3, and omega-6 polyunsaturated fatty acids due to established evidence in the literature of a link between atherosclerotic disease and major depression. We argue that there is significant potential scope for the use of such peripheral biomarkers in the diagnosis, stratification and treatment of MDD.