Spatially compartmentalized phase regulation of a Ca²⁺-cAMP-PKA oscillatory circuit

Abstract

Signaling networks are spatiotemporally organized in order to sense diverse inputs, process information, and carry out specific cellular tasks. In pancreatic β cells, Ca 2+ , cyclic adenosine monophosphate (cAMP), and Protein Kinase A (PKA) exist in an oscillatory circuit characterized by a high degree of feedback, which allows for specific signaling controls based on the oscillation frequencies. Here, we describe a novel mode of regulation within this circuit involving a spatial dependence of the relative phase between cAMP, PKA, and Ca 2+ . We show that nanodomain clustering of Ca 2+ -sensitive adenylyl cyclases drives oscillations of local cAMP levels to be precisely in-phase with Ca 2+ oscillations, whereas Ca 2+ -sensitive phosphodiesterases 2 maintain out-of-phase oscillations outside of the nanodomain, representing a striking example and novel mechanism of cAMP compartmentation. Disruption of this precise in-phase relationship perturbs Ca 2+ oscillations, suggesting that the relative phase within an oscillatory circuit can encode specific functional information. This example of a signaling nanodomain utilized for localized tuning of an oscillatory circuit has broad implications for the spatiotemporal regulation of signaling networks.

AKAP79/150 coordinates leptin-induced PKA signaling to regulate KATP channel trafficking in pancreatic β-cells

“…Rather, AMPK may act via ACs either directly or indirectly to cause a rise in cAMP. Indeed, several ACs have been reported to interact with AKAP79/ 150 (21,(60)(61)(62)(63)(64). Of note, we observed a small but significant increase in cAMP detected by the cytosolic AKAP18CUTie in response to forskolin stimulation in leptin-treated cells compared with vehicle-treated cells; this raises the possibility that leptin may also enhance forskolin-induced AC activation in the cytosol, although the significance of this observation awaits further investigation.…”

DrFLINC Contextualizes Super-resolution Activity Imaging

“…Nanoclusters of AKAP79 molecules were observed on the plasma membrane, a majority of which were colocalized with PKA activity microdomains (Figure 4A/D and Figure S9A), confirming the presence of AKAP mediated PKA activity architecture in living cells. AKAP nano-clustering likely plays a critical role in organizing this activity architecture, not only by increasing the effective concentration of PKA regulatory subunits to enable micro-compartmentalized PKA activity 3 but also by recruiting and concentrating adenylyl cyclases 19 .…”

Messages across time and space

“…So far, however, it remains unclear how the spatial organization of these highly diffusible molecules is achieved. Now, in eLife, Jin Zhang and colleagues from the University of California, San Diego – including Brian Tenner as first author – report new insights into second messenger oscillations ( Tenner et al, 2020 ).…”