AKAP10

AKAP10 (D-AKAP2) is a dual-specific A-kinase anchoring protein that organizes compartmentalized PKA signaling at mitochondria and the endocytic recycling system (PMID:11248059, PMID:19797056). It anchors both type I (RIα) and type II (RIIα) PKA regulatory subunits through a C-terminal amphipathic helix that engages the dimerization/docking domains of each subunit, with dual specificity arising from a register shift in how the AKAP helix packs against RIα versus RIIα (PMID:9326583, PMID:20159461). Beyond PKA, AKAP10 nucleates a polyvalent membrane scaffold: a C-terminal PDZ-binding motif recruits PDZK1 (and to a lesser extent NHERF-1), and high-affinity PDZK1 engagement requires prior formation of the AKAP10:PKA complex, coupling kinase anchoring to transporter regulation (PMID:14531807, PMID:25348485). Its N-terminal tandem RGS domains bind GTP-loaded Rab4 and Rab11 and promote accumulation of recycling cargo such as the transferrin receptor in the Rab4/Rab11-positive recycling compartment (PMID:19797056). In vivo, disruption of the AKAP10 C-terminus in mice heightens cholinergic cardiac responses and produces arrhythmias, establishing AKAP10 as a regulator of cardiac rhythm through the autonomic signaling pathway (PMID:17485678).

1. 1997 Medium

   Established AKAP10 as a dual-specific AKAP, answering whether a single anchoring protein could bind both PKA isoform classes and hinting at an additional RGS module.

   Evidence Yeast two-hybrid and coprecipitation mapping the C-terminal R-binding domain against RIα and RIIα dimerization domains

   PMID:9326583

   Open questions at the time

   • Structural basis of dual specificity not resolved
   • RGS domain function and binding partners unknown
   • Subcellular localization not addressed
2. 2001 High

   Defined where AKAP10 acts in the cell, localizing it to mitochondria and confirming endogenous PKA association in vivo.

   Evidence Immunocytochemistry, immunohistochemistry, subcellular fractionation across three species, and cAMP-agarose pull-down from mouse brain

   PMID:11248059

   Open questions at the time

   • Mechanism of mitochondrial targeting not defined
   • Functional consequence of mitochondrial PKA anchoring not tested
3. 2002 Medium

   Resolved the domain architecture, distinguishing a folded N-terminal RGS domain from a C-terminal region carrying the protected PKA site and accessible PDZ motif within disordered flanks.

   Evidence Deuterium exchange-mass spectrometry and limited proteolysis

   PMID:12206784

   Open questions at the time

   • No atomic structure
   • Functional roles of the disordered regions not established
4. 2003 Medium

   Identified the PDZ-binding motif's partner, linking AKAP10/PKA to scaffold proteins that organize membrane transporters in renal tubular cells.

   Evidence Yeast two-hybrid, pull-down, and co-immunoprecipitation from transfected opossum kidney cells

   PMID:14531807

   Open questions at the time

   • Single lab, single cell context
   • Hierarchy of PKA vs PDZK1 binding not yet defined
5. 2007 Medium

   Connected AKAP10 to organismal physiology, showing its C-terminus regulates cholinergic cardiac signaling and heart rhythm.

   Evidence Gene-trap disruption in mouse ES-derived cardiomyocytes and in vivo cardiac physiology

   PMID:17485678

   Open questions at the time

   • Molecular link between anchoring and arrhythmia not delineated
   • Specific PKA targets in cardiomyocytes not identified
6. 2009 High

   Assigned a function to the tandem RGS domains, revealing the first RGS–small-GTPase interaction and a role in endocytic recycling.

   Evidence Co-immunoprecipitation with Rab4/Rab11 plus RNAi knockdown with quantitative transferrin recycling assay and colocalization imaging

   PMID:19797056

   Open questions at the time

   • Whether GTPase activity is modulated (GAP/effector role) not resolved
   • Integration of recycling role with PKA anchoring not tested
7. 2014 High

   Explained how the scaffold assembles, showing ordered binding of PKA precedes high-affinity PDZK1 recruitment to nucleate a polyvalent complex.

   Evidence X-ray crystallography of the AKAP10:PKA RII:PDZK1 ternary complex with binding analysis

   PMID:25348485

   Open questions at the time

   • Full-length scaffold architecture including RGS domains not captured
   • Stoichiometry in native membranes not determined

• How the mitochondrial PKA anchoring, the Rab-dependent recycling function, and the transporter-scaffolding activity are coordinated within a single signaling unit remains unresolved.
• No integrated model linking the RGS, PKA, and PDZ functions
• Cardiac substrate(s) downstream of AKAP10 unknown