Subcellular Organization of the cAMP Signaling Pathway

Abstract

The field of cAMP signaling is witnessing exciting developments with the recognition that cAMP is compartmentalized and that spatial regulation of cAMP is critical for faithful signal coding. This realization has changed our understanding of cAMP signaling from a model in which cAMP connects a receptor at the plasma membrane to an intracellular effector in a linear pathway to a model in which cAMP signals propagate within a complex network of alternative branches and the specific functional outcome strictly depends on local regulation of cAMP levels and on selective activation of a limited number of branches within the network. In this review, we cover some of the early studies and summarize more recent evidence supporting the model of compartmentalized cAMP signaling, and we discuss how this knowledge is starting to provide original mechanistic insight into cell physiology and a novel framework for the identification of disease mechanisms that potentially opens new avenues for therapeutic interventions. SIGNIFICANCE STATEMENT: cAMP mediates the intracellular response to multiple hormones and neurotransmitters. Signal fidelity and accurate coordination of a plethora of different cellular functions is achieved via organization of multiprotein signalosomes and cAMP compartmentalization in subcellular nanodomains. Defining the organization and regulation of subcellular cAMP nanocompartments is necessary if we want to understand the complex functional ramifications of pharmacological treatments that target G protein-coupled receptors and for generating a blueprint that can be used to develop precision medicine interventions.

Graphical abstract

Fig. 1.

Plasma membrane and primary cilium cAMP signalosomes. A selection of the signalosomes that localize at the plasma membrane and primary cilium are illustrated. PKA-dependent phosphorylation is indicated in yellow. The cellular function that each signalosome controls is indicated by the gray arrows. Ub indicates ubiquitination. The red gradient indicates cAMP. The white halo surrounding the phosphodiesterases indicates reduced local concentration of cAMP. For details of the different protein components, see the main text. I_Ca, calcium current; I_Cl, cloride current; I_Na, sodium current; Hh, hedgehog protein; NHERF1, Na⁺/H⁺ exchanger regulatory factor 1; P, phosphate group; PCM1, pericentriolar material 1; SAP-97, synapse-associated protein 97.

Fig. 2.

Mitochondrial cAMP signalosomes. Multiple cAMP signalosomes localize to the mitochondria. Red gradients illustrate cAMP. The MOM is permeable to cytosolic cAMP, whereas the MIM is not. In the matrix, AC10 generates the second messenger locally. For the individual protein components of the signalosomes, see the main text. GK, glucokinase; P, phosphate group; PTPD1, protein tyrosine phosphatase D1; SAM50, sorting and assembly machinery component; StAR, steroidogenesis acute regulatory protein; TSPO, translocator protein; VDAC-1, voltage-dependent anion channel 1.

Fig. 3.

cAMP signalosomes at the endoplasmic reticulum, nucleus, and centrosome. For clarity, multiprotein complexes illustrated here may not include all components that have been described in the literature. For identification of individual protein components, please refer to the main text. The red gradient illustrating cAMP highlights the fact that the nuclear membrane is permeable to cAMP, whereas the ER membrane is not. Lighter red halos surrounding PDEs indicate low local cAMP. P, phosphate group; SEC24, secretion 24.