cAMP signaling in subcellular compartments

Abstract

In the complex microcosm of a cell, information security and its faithful transmission are critical for maintaining internal stability. To achieve a coordinated response of all its parts to any stimulus the cell must protect the information received from potentially confounding signals. Physical segregation of the information transmission chain ensures that only the entities able to perform the encoded task have access to the relevant information. The cAMP intracellular signaling pathway is an important system for signal transmission responsible for the ancestral ‘flight or fight’ response and involved in the control of critical functions including frequency and strength of heart contraction, energy metabolism and gene transcription. It is becoming increasingly apparent that the cAMP signaling pathway uses compartmentalization as a strategy for coordinating the large number of key cellular functions under its control. Spatial confinement allows the formation of cAMP signaling “hot spots” at discrete subcellular domains in response to specific stimuli, bringing the information in proximity to the relevant effectors and their recipients, thus achieving specificity of action. In this report we discuss how the different constituents of the cAMP pathway are targeted and participate in the formation of cAMP compartmentalized signaling events. We illustrate a few examples of localized cAMP signaling, with a particular focus on the nucleus, the sarcoplasmic reticulum and the mitochondria. Finally, we discuss the therapeutic potential of interventions designed to perturb specific cAMP cascades locally.

Regulation of Mitochondrial Poly(ADP-Ribose) Polymerase Activation by theβ-Adrenoceptor/cAMP/Protein Kinase A Axis during Oxidative Stress

“…Although many additional details of the underlying mechanisms remain to be explored, the current findings may have implications for a number of cellular processes that are known to be regulated by PARP1, including cellular metabolism and DNA repair, given the fact that both of these processes can be regulated by the b-adrenoceptor/cAMP system (Carlucci et al, 2008;Cho and Juhnn, 2012;Valsecchi et al, 2013;Lefkimmiatis and Zaccolo, 2014). However, these aspects remain to be directly investigated in further studies.…”

“…It must be pointed out that multiple lines of data indicate that the cytosolic and mitochondrial cAMP pools do not communicate in most cases. At the same time, several sets of data also indicate that cell membrane and cytosolic signals can elevate intramitochondrial PKA activity, followed by phosphorylation of intramitochondrial proteins (reviewed in Lefkimmiatis and Zaccolo, 2014). Yet another possibility may be the extramitochondrial phosphorylation of PARP1, followed by its transport into the mitochondria, even though the early time course of extranuclear PARP1 phosphorylation (see Fig.…”

Cyclic AMP Signaling Reduces Sirtuin 6 Expression in Non-small Cell Lung Cancer Cells by Promoting Ubiquitin-Proteasomal Degradation via Inhibition of the Raf-MEK-ERK (Raf/Mitogen-activated Extracellular Signal-regulated Kinase/Extracellular Signal-regulated Kinase) Pathway

“…Cyclic nucleotide phosphodiesterases degrade cAMP to 5Ј-AMP. cAMP binds to and activates cAMPdependent protein kinase (PKA), exchange factor directly activated by cAMP (EPAC), and cyclic-nucleotide-gated ion channels (CNG) (5). Activated PKA phosphorylates enzymes to regulate both metabolism and transcription factors such as cyclic AMP response element binding protein (CREB).…”

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

“…AKAPs play roles in many more cellular processes whose dysregulation leads to disease. They are involved in complex mechanisms such as memory formation and blood pressure control [161,262,263] and tether different protein assemblies to various subcellular compartments [264]. Thus AKAPs are a rich source to be considered as pharmacological targets.…”