AKAP6β – A Conductor in the Orchestra of Pathological Cardiomyocyte Gene Transcription

Figures

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  Fig. 1.. AKAP6 domain structure. Because of alternative splicing, AKAP6β is identical to AKAP6α amino acids (aa) 245–2314 (rat numbering). AKAP6β domains for which binding sites have been defined are shown.16,19,20,25,26,28,30–33 HDAC, histone deacetylase. Created in BioRender. Kapiloff (2026). https://bioRender.com/jn7njwv.

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  Fig. 2.. AKAP6β-mediated PKA signaling. The AKAP6β signalosome binds adenylyl cyclase type 5, the cAMP effectors PKA and Epac1, and the PDE4D3, allowing for cAMP to be produced, used, and degraded in the same intracellular compartment.16,29,32,33 PKA phosphorylation of PDE4D3 and the B56δ subunit of PP2A results in increased phosphodiesterase and phosphatase activity, respectively. Epac1-dependent ERK5 phosphorylates and inhibits PDE4D3. Created in BioRender. Kapiloff (2026). https://bioRender.com/5iiq4sp.

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  Fig. 3.. Calcium signaling orchestrated by the AKAP6β signalosome. AKAP6β orchestrates a perinuclear calcium microdomain in the cardiomyocyte via the phosphorylation of perinuclear type 2 Ryanodine receptor, allowing for the persistent activation of the calcium/calmodulin-dependent phosphatase calcineurin. In turn, AKAP6β-bound calcineurin dephosphorylates the transcription factors NFAT and MEF2, inducing pathological gene transcription.24,25,28,45 The location of perinuclear RyR2 associated with AKAP6β complexes remains unclear. Created in BioRender. Kapiloff (2026). https://BioRender.com/z9kswn8.

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  Fig. 4.. Regulation of the transcription factor SRF by AKAP6β signalosomes. The association of RSK3, PP2A, and the transcription factor SRF with the AKAP6β signalosome facilitates the directional regulation of SRF serine-103 phosphorylation by RSK3 and PP2A.8 Phosphorylated SRF exhibits SRF DNA binding activity and, through select enhancers, promotes pathological concentric cardiac hypertrophy. At AKAP6β, RSK3 is regulated by ERK-RSK3 signaling and PP2A by PKA signaling. MEK, mitogen activated protein kinase; MEKK, Mitogen activated protein kinase kinase; MRTF-A/B, myocardin-related transcription factor A/B; PDK1, 3-phosphoinositide-dependent protein kinase-1. Created in BioRender. Kapiloff (2026). https://BioRender.com/ta5hopx.

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  Fig. 5.. AKAP6β-Golgi interactions. Nesprin-1α-AKAP6β-AKAP9-GM130 form a bridge between the outer nuclear membrane and facing Golgi.19 AKAP6β is localized to the outer nuclear envelope via its SR3 domain binding to nesprin-1α.20 The SR1 domain on AKAP6β binds to the Golgi-localized PACT/AKAP9 protein complex.19 Golgi-localized β1ARs regulate cardiac hypertrophy via activation of AKAP6β signalosomes.9 KASH, Klarsicht/nuclear anchorage protein-1/syne homology; PACT domain, pericentrin-AKAP450 centrosomal targeting; SUN, Sad1p/UNC84 domain-containing protein. Created in BioRender. Kapiloff (2026) https://BioRender.com/j2jm8z4.