Calcineurin–AKAP interactions: therapeutic targeting of a pleiotropic enzyme with a little help from its friends

Abstract

The ubiquitous Ca 2+ /calmodulin-dependent phosphatase calcineurin is a key regulator of pathological cardiac hypertrophy whose therapeutic targeting in heart disease has been elusive due to its role in other essential biological processes. Calcineurin is targeted to diverse intracellular compartments by association with scaffold proteins, including by multivalent A-kinase anchoring proteins (AKAPs) that bind protein kinase A and other important signalling enzymes determining cardiac myocyte function and phenotype. Calcineurin anchoring by AKAPs confers specificity to calcineurin function in the cardiac myocyte. Targeting of calcineurin 'signalosomes' may provide a rationale for inhibiting the phosphatase in disease.Kimberly Dodge-Kafka has been at the University of Connecticut Health Center since 2003, where she is currently and Associate Professor of Cell Biology. Her research combines, biochemical, cellular and physiological approaches to investigate the role of scaffolding proteins in modulating the signalling pathways involved in the induction of cardiac disease. Michael S. Kapiloff is an Associate Professor at Stanford University where his laboratory studies the basic molecular mechanisms underlying the response of the cardiac myocyte and retinal ganglion cell to pathological stress and how these concepts may be translated into new therapies. He is a Fellow of the American Physiological Society and American Heart Association and a member of the American Society for Clinical Investigation.

Compartmentalized cAMP signalling and control of cardiac rhythm

“…The fact that different phosphatases associate with individual signalosomes provides further complexity to the regulation of cAMP signals by enabling additional local variation in the signal dynamics. In the heart, protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) catalyse between 70% and 90% of all dephosphorylation events [ 91 ], although protein phosphatase 2B (PP2B) (calcineurin, CaN) also contributes [ 92 ]. The number of phosphatases is significantly smaller than the number of targets they dephosphorylate and substrate specificity primarily relies on the role of regulatory subunit, which also dictate their subcellular localization [ 93 ].…”

mAKAPβ signalosome: A potential target for cardiac hypertrophy

“…PKA, Protein Kinase A. complex. Activated CaNAβ dephosphorylates NFATc serine rich residues at the N-terminal (Gildart et al, 2020;Wu et al, 2007). All the isoforms of NFATc contribute to the induction of cardiac remodeling.…”

“…Increased Ca +2 levels bind to calcineurin on the signalosome and further activate CaNAβ catalytic site by binding of Ca +2 ‐Calmodulin complex. Activated CaNAβ dephosphorylates NFATc serine rich residues at the N‐terminal (Gildart et al, 2020; Wu et al, 2007). All the isoforms of NFATc contribute to the induction of cardiac remodeling.…”

AKAP79 enables calcineurin to directly suppress protein kinase A activity

“…Anchoring proteins support signal transduction by elevating effective local concentrations of signaling proteins, and therefore theoretically an AKAP might support pRII dephosphorylation by CN in cells ( Gildart et al, 2020 ). A-kinase anchoring protein 79 (AKAP79; rodent ortholog AKAP150, gene name AKAP5) is a prototypical mammalian anchoring protein with several features that indicate it could operate in part by increasing the effective protein concentration of pRII subunits for CN.…”