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By limiting unrestricted activation of intracellular effectors, compartmentalized signaling of cyclic nucleotides confers specificity to extracellular stimuli and is critical for the development and health of cells and organisms. Dissecting the molecular mechanisms that allow local control of cyclic nucleotide signaling is essential for our understanding of physiology and pathophysiology, but mapping the dynamics and regulation of compartmentalized signaling is a challenge. In this minireview we summarize advanced imaging and proteomics techniques that have been successfully used to probe compartmentalized cAMP signaling in eukaryotic cells. Subcellularly targeted fluorescence resonance energy transfer sensors can precisely locate and measure compartmentalized cAMP, and this allows us to estimate the range of effector activation. Because cAMP effector proteins often cluster together with their targets and cAMP regulatory proteins to form discrete cAMP signalosomes, proteomics and phosphoproteomics analysis have more recently been used to identify additional players in the cAMP-signaling cascade. We propose that the synergistic use of the techniques discussed could prove fruitful in generating a detailed map of cAMP signalosomes and reveal new details of compartmentalized signaling. Compiling a dynamic map of cAMP nanodomains in defined cell types would establish a blueprint for better understanding the alteration of signaling compartments associated with disease and would provide a molecular basis for targeted therapeutic strategies. SIGNIFICANCE STATEMENT: cAMP signaling is compartmentalized. Some functionally important cellular signaling compartments operate on a nanometer scale, and their integrity is essential to maintain cellular function and appropriate responses to extracellular stimuli. Compartmentalized signaling provides an opportunity for precision medicine interventions. Our detailed understanding of the composition, function, and regulation of cAMP-signaling nanodomains in health and disease is essential and will benefit from harnessing the right combination of advanced biochemical and imaging techniques.

Axelrod Symposium 2019: Phosphoproteomic Analysis of G-Protein–Coupled Pathways