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

Abstract

The ubiquitous Ca²⁺/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 biologic processes. Calcineurin is targeted to diverse intracellular compartments by association with scaffold proteins, including by multivalent A‐kinase anchoring proteins (AKAPs) that bind PKA and other important signaling 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.

Proposed targeting of Calcineurin/AKAP complexes. By using peptide displacement to compete for Calcineurin binding to AKAPs, we may be able to prevent its downstream functions including induction of cardiac disease.

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