Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins

  1. Kjetil Taskén
  1. Biotechnology Centre of Oslo and Centre for Molecular Medicine, Nordic EMBL Partnership, University of Oslo, PO Box 1125, Blindern, N-0317 Oslo, Norway
  1. (Correspondence should be addressed to K Taskén; Email: kjetil.tasken{at}biotek.uio.no)
  1. Figure 1

    cAMP signal pathways. Ligand binding to various G protein-coupled receptors (GPCRs) activates adenylyl cyclase in their proximity and generates pools of cAMP. The local concentration and distribution of the cAMP gradient are limited by phosphodiesterases (PDEs). Particular GPCRs are confined to specific domains of the cell membrane in association with intracellular organelles or cytoskeletal constituents. The subcellular structures may harbor specific isozymes of PKA that, through anchoring via AKAPs, are localized in the vicinity of the receptor and the cyclase. PDEs are also anchored and serve to limit the extension and duration of cAMP gradients. These mechanisms serve to localize and limit the assembly and triggering of specific pathways to a defined area of the cell close to the substrate. cAMP (red filled circles) has effects on a range of effector molecules encompassing 1) PKA, 2) PDEs, 3) guanine nucleotide exchange factors (GEFs) known as exchange proteins activated by cAMP (Epacs), and 4) cyclic nucleotide-gated ion channels.

  2. Figure 2

    Illustration of AKAP properties. (A) AKAPs share three common properties: 1) AKAPs bind to the regulatory subunit of PKA through a conserved anchoring domain; 2) a unique subcellular targeting domain directs AKAP-signaling complexes to discrete locations inside a cell; and 3) additional binding sites for other signaling proteins such as kinases, phosphatases, or potential substrates. (B) Ribbon diagram of the NMR structure of RIIα (1–43) dimer (yellow, blue, and red) and the AKAP amphipathic helix peptide (green; Newlon et al. 2001) depicted using Accelrys Discovery Studio 2.5.1 based on the coordinates from PDB (http://www.rcsb.org/pdb/explore/explore.do?structureId=2DRN).

  3. Figure 3

    Comparison of the RIα and the RIIα D/D domains (Newlon et al. 2001, Banky et al. 2003). NMR structures were depicted using Accelrys Discovery Studio 2.5.1 based on the coordinates from PDB (for RI: 2EZW; http://www.rcsb.org/pdb/explore/explore.do?structureId=2EZW; and for RII: 2DRN, http://www.rcsb.org/pdb/explore/explore.do?structureId=2DRN). The extreme N-termini are shown in yellow, helices A and A′ in blue, and helices B and B′ in red respectively.

  4. Figure 4

    Schematic illustration of the effect of specific anchoring disruptor peptides. (A) Model of type I PKA and type II PKA signal complexes organized by specific AKAPs and mediating biological effects 1 and 2 respectively. (B and C) Models for effect of RIAD or SuperAKAP-IS on biological effects 1 and 2. (D and E) Effect of RIAD and SuperAKAP-IS together or Ht31 on biological effects 1 and 2. cAMP, red-filled circles; phosphate, blue-filled circles.

  5. Figure 5

    Signal complex consisting of mAKAP, PKA, PDE4D3, Epac, and a MEKK/MEK5/ERK5 module. mAKAP anchors PKA and PDE4D3, whereas PDE4D3 scaffolds an Epac–Rap1 pathway that coordinates a MEKK/MEK5/ERK5 module. cAMP, red-filled circle; phosphate, blue-filled circle.

  6. Figure 6

    PKA–AKAP18δ–PLB–SERCA2 complex. (A) Resting situation, no adrenergic drive, low heart rate, SERCA2 inhibited by PLB with low ATP and energy consumption. (B) Adrenergic stimulation paces the heart and increased heart rate. SERCA2 released from PLB inhibition by PKA phosphorylation leading to fast Ca2+ reabsorption and high ATP and energy consumption.

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