cAMP: From Long-Range Second Messenger to Nanodomain Signalling

Abstract

How cAMP generates hormone-specific effects has been debated for many decades. Fluorescence resonance energy transfer (FRET)-based sensors for cAMP allow real-time imaging of the second messenger in intact cells with high spatiotemporal resolution. This technology has made it possible to directly demonstrate that cAMP signals are compartmentalised. The details of such signal compartmentalisation are still being uncovered, and recent findings reveal a previously unsuspected submicroscopic heterogeneity of intracellular cAMP. A model is emerging where specificity depends on compartmentalisation and where the physiologically relevant signals are those that occur within confined nanodomains, rather than bulk changes in cytosolic cAMP. These findings subvert the classical notion of cAMP signalling and provide a new framework for the development of targeted therapeutic approaches.

Aspects of astrocytic cAMP signaling with an emphasis on the putative power of compartmentalized signals in health and disease

“…As for Ca 2+ biosensors, transgenic animals expressing a targeted cAMP biosensor have been produced and successfully employed to study a cAMP microdomain in proximity to SERCA pumps in cardiac myocytes (Sprenger et al, ). Thus, the real‐time imaging of cAMP is now more an issue about which targeted sensor is employed and which subcellular organization of the multifunctional cAMP signaling pathway wished to be investigated (Musheshe et al, , Surdo et al, ).…”

“…This timeline gives an overview of the cAMP and Ca 2+ methodological progresses from discovery to present including some representative references. Data for timeline as reported in literature (for detailed cAMP reporters see Jiang, Falcone, Curci, and Hofer (); Musheshe, Schmidt, and Zaccolo (); Paramonov, Mamaeva, Sahlgren, and Rivero‐Muller (); Schleicher and Zaccolo ()) (for Ca2+ see Campbell (); Grienberger and Konnerth (); Looger and Griesbeck (); Suzuki, Kanemaru, and Iino ()). ∧ , Salomon, Londos, and Rodbell (); Г , Takeda, Kuno, Shuntoh, and Tanaka (); ᶳ, Nordstedt and Fredholm (); °, Adams, Harootunian, Buechler, Taylor, and Tsien (); ¤ , Zaccolo et al (); Zaccolo and Pozzan (); ¥ , DiPilato et al (); Nikolaev, Bunemann, Hein, Hannawacker, and Lohse (); Ponsioen et al (); ₽ , Nikolaev et al ()ᶤ, Everett and Cooper (); + , Sprenger et al (); £ , Vergara and Delay (); *, Grynkiewicz, Poenie, and Tsien (); ҍ , Tsien, Rink, and Poenie (); ᶬ, Kendall, Sala‐Newby, Ghalaut, Dormer, and Campbell (); ᶣ, Romoser, Hinkle, and Persechini (); ᶲ, Miyawaki et al (); ᶿ, Nakai, Ohkura, and Imoto (); Sawano and Miyawaki (); Ω , Wang, Wong, Flores, Vosshall, and Axel (); Ⅎ , Ji et al (); ⋔ , Tallini et al (); ℓ , Willoughby, Wachten, Masada, and Cooper (); †, Dana et al ().…”

“…Abbreviations: AC, adenylyl cyclase; Epac, exchange protein directly activated by cAMP; GECI, genetically encoded Ca 2+ indicators; HCN2, hyperpolarizationactivated cyclic nucleotide-gated channel 2; PEI, polyethyleneimine; PKA, protein kinase A; PLN, phospholamban; PM, plasma membrane; smGC, smooth muscle isoform of myosin heavy chain-GCaMP1 expressing mice expressing a targeted cAMP biosensor have been produced and successfully employed to study a cAMP microdomain in proximity to SERCA pumps in cardiac myocytes (Sprenger et al, 2015). Thus, the real-time imaging of cAMP is now more an issue about which targeted sensor is employed and which subcellular organization of the multifunctional cAMP signaling pathway wished to be investigated (Musheshe et al, 2018, Surdo et al, 2017.…”

Function of cAMP scaffolds in obstructive lung disease: Focus on epithelial‐to‐mesenchymal transition and oxidative stress

“…It will therefore be of interest in the future to study the extent to which distinct ACs (Halls & Cooper, 2017), acting in concert with a distinct subset of PDEs, PKA, and Epac, may contribute to the differential regulation of ECM deposition. Even though such cAMP microdomains have been extensively studied in the cardiovascular system (Laudette et al, 2018;Musheshe, Schmidt, & Zaccolo, 2018), they still have to be defined in more detail in the pulmonary system.…”

“…As one of the best known second messengers, cAMP transmits the information carried by hormones, neurotransmitters, and other extracellular signals into the intracellular environment (Berthet et al, 1957;Musheshe et al, 2018). As one of the main bronchodilator therapies, β 2 -adrenoceptor agonists augment the anti-inflammatory effects of corticosteroids in obstructive lung diseases (Barnes et al, 2015;Maji et al, 2018;Vogelmeier et al, 2017;Wang et al, 2018).…”