AKAP12 Signaling Complex: Impacts of Compartmentalizing cAMP‐Dependent Signaling Pathways in the Heart and Various Signaling Systems

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  Figure 1. Role of AKAP13 in cardiac function. GPCR signaling is directed by the type of ligand binding to this receptor. The nature of the ligand would favorably shift the equilibrium to a specific conformation of the receptor, which signals through a distinct G protein. For AKAP13 and GPCR signaling in the heart, it has been associated with 2 distinct G protein–signaling pathways (Gα12 and Gαs). A, When stimulation of β‐AR stabilizes its conformation to signal through Gα12, AKAP13 signalosome is attracted near the receptor. AKAP13 interacts with Gα12 allowing Rho‐GEF stimulation. Upon Rho‐GEF stimulation, both SRF (Rho‐GEF guanosine triphosphatase) and myocyte enhancer factor 2C (transcription factor) activities are increased. However, the mechanism of their activation depends on different regions of AKAP13. Activation of myocyte enhancer factor 2C depends on the carboxyl region of AKAP13 (BRX), whereas SRF activation depends on the GEF region of AKAP13. Collectively, this suggests that increased gene expression of factors associated with cardiac development may be partially dependent on AKAP13.65 B, AKAP13 has been reported in the cardiac hypertrophic signaling. Under states of increased…

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  Figure 2. Role of AKAP complexes in cardiac contractility. Cardiac contractility is controlled mainly by the delicate interplay between RyR, calcium channels (Ca2+ v1.2), SR, and SERCA. On electrical stimulation, the voltage‐gated Ca2+ channels increase Ca2+ influx, leading to local areas of high Ca2+ (1). The local increase of Ca2+ activates the RyR channels located on the SR (2). The RyR channels activation increases Ca2+ efflux from the SR, causing a cytosolic (global) increased Ca2+ (3). The global increase in Ca2+ triggers muscle contraction cycle, as a result of Ca2+ binding to troponin (4). SERCA plays a major role in maintaining consistency in the contractile force between cardiac beats. As a response to high cytosolic levels of Ca2+, SERCA reuptakes Ca2+ back into the SR to return to baseline levels in the cytoplasm. SERCA activity is controlled by PLN, which, when phosphorylated by PKA, allows SERCA to reuptake Ca2+. AKAPs play a crucial role in each of these phases; AKAP15/18 facilitates Ca2+ influx through targeting PKA to the C terminus of Ca2+ v1.2 channels, AKAP79/150 binds PKA and PKCα to Cav1.2 channels to facilitate their normal gating, and AKAP18δ mediates PKA…

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  Figure 3. AKAP12 schematic topological map shows the known and potential protein–protein binding and phosphorylation domains. 2–7 coiled coils indicates 2–7 alpha‐helices usually involved in gene expression102, 103, 104β2‐AR indicates β2‐adrenergic receptor; BD, binding domain; EGF, epidermal growth factor; GalTase, β‐1,4‐galactosyltransferase; PKA, protein kinase A; PKC, protein kinase C; SRC, non‐receptor tyrosine kinase; and WSK, short motifs composed of 3 conserved residues found in a WXSXK motif.

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  Figure 4. Proposed AKAP12 signaling downstream of β2‐AR. AKAP12 scaffolds multiple kinases, in addition to polybasic domains, which control its interactions and signaling. Under the unstimulated β2‐AR state, AKAP12 is found mainly within the cytoplasm. However, when β2‐AR is stimulated, the polybasic domains found within the AKAP12 signalosome targets the complex to the cell membrane. This colocalization of the signalosome facilitates a stable binding of β2‐AR and AKAP12. Activation of PKA is associated with increased levels of cAMP in its proximity. β2‐AR stimulation induces local increases of cAMP. AKAP12 is important for PKA activation through scaffolding and collocating PKA near areas of high cAMP levels. The active form of PKA phosphorylates multiple downstream molecules, such as CREB (cellular transcription factor), SRC (tyrosine kinase), and GRK (G protein kinases), all playing a role in downstream signaling of β2‐AR. Importantly, PKA phosphorylates AKAP12, which stabilizes the interaction between AKAP12 and the β2‐AR, even during post‐internalization of the receptor.102 On the other hand, phosphorylation of AKAP12 by PKC decreases AKAP12–PKC scaffolding (1),99 inhibits the…