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.

Keywords: AKAPs; Compartmentalization; PDEs; PKA; Signaling; cAMP.

Figure 1. cAMP-PKA signalosomes at the Sarcoplasmic Reticulum

The schematic shows two signalosomes found at the SR, formed around AKAP18δ and mAKAP (left side and right side respectively). AKAP18δ recruits PKA type II near the complex SERCA/PLN. In basal conditions PDE3A and PDE4D maintain cAMP levels low and PKA inactive. In response to increased cAMP levels (e.g. during catecolamine-dependent signaling) PKA is activated and free to phosphorylate PLN. Phopshorylated PLN can not efficiently repress the function of SERCA allowing for more efficient Ca2⁺ refill of the SR. The local signal is terminated by the coordinated action of PDEs and protein phopshatases (PP2A). Similarly, mAKAP acts as platform for a cAMP-responsive signalosome comprised of PKA type II; PDE4D3; PP1 and PP2A. This multiprotein complex was shown to localize in proximity and phophorylate the Ca2⁺-channel ryanodine receptor.

Figure 2. Mitochondrial AKAPs

The inter membrane space contains the PKA type I-specific AKAP named SKIP. PKA tethered at the inter membrane space via SKIP can phopshorylate the protein chchd3. At the outer mitochondrial membrane are found 3 different AKAPs, Rab32; AKAP2 and AKAP121. AKAP2 and AKAP121 can form complexes with PKA type I and type II while Rab32 can complex only with PKA type II. One of the well-characterized targets of AKAP121-bound PKA is the fission regulator Drp1. Phopshorylated forms of Drp1 can not promotes mitochondrial fission therefore high PKA activity at the outer mitochondrial membrane blocks mitochondrial fission resulting in elongated organelles.