Potential therapeutic applications of AKAP disrupting peptides

Abstract

The 3′–5′-cyclic adenosine monophosphate (cAMP)/PKA pathway represents a major target for pharmacological intervention in multiple disease conditions. Although the last decade saw the concept of highly compartmentalized cAMP/PKA signaling consolidating, current means for the manipulation of this pathway still do not allow to specifically intervene on discrete cAMP/PKA microdomains. Since compartmentalization is crucial for action specificity, identifying new tools that allow local modulation of cAMP/PKA responses is an urgent need. Among key players of cAMP/PKA signaling compartmentalization, a major role is played by A-kinase anchoring proteins (AKAPs) that, by definition, anchor PKA, its substrates and its regulators within multiprotein complexes in well-confined subcellular compartments. Different tools have been conceived to interfere with AKAP-based protein–protein interactions (PPIs), and these primarily include peptides and peptidomimetics that disrupt AKAP-directed multiprotein complexes. While these molecules have been extensively used to understand the molecular mechanisms behind AKAP function in pathophysiological processes, less attention has been devoted to their potential application for therapy. In this review, we will discuss how AKAP-based PPIs can be pharmacologically targeted by synthetic peptides and peptidomimetics.

It Takes Two to Tango! Protein–Protein Interactions behind cAMP-Mediated CFTR Regulation

“…Disruption of Shank2 and CFTR n/a Shank2 overexpression has been shown to CFTR activity by 50% in NIH3T3 cells, hence disruption of Shank2/CFTR interaction could be a potential strategy for enhancing CFTR activity [11,38,72] Selective inhibition of the A-kinase anchoring protein function of PI3Kγ; inhibition of cAMP degradation…”

“…The activity of cAMP signalosomes, and in particular of PKA, is also spatially regulated by A-kinase anchoring proteins (AKAPs). AKAPs are a diversified group of scaffold proteins that, by binding directly to the regulatory subunits of PKA, recruit the holoenzyme to specific cellular structures, such as cytoskeletal components, close to their phosphorylation targets [ 11 ]. In addition to PKA, AKAPs can interact with other players in cAMP signaling and, even with different signal transduction machineries, act as crossroads for different signaling pathways [ 11 ].…”

“…A promising candidate is the signaling cascade orchestrated by 3′,5′-cyclic adenosine monophosphate (cAMP), since this second messenger can regulate multiple aspects of CFTR function, from channel open probability to its localization in the plasma membrane [ 10 ]. More importantly, as discussed briefly in the following paragraph, cAMP is compartmentalized in space and time thanks to the formation of localized signaling complexes, also known as cAMP signalosomes, anchored to specific subcellular compartments or organelles within the cell, and thus represents an ideal target for fine-tuned therapeutic approaches [ 11 ].…”

Regulation of cardiac function by cAMP nanodomains

“…A peptide named ‘PLN peptide’ disrupts the interaction between AKAP18δ and PLN [ 77 ]. Although this would be of limited use in HF, as PLN phosphorylation is down-regulated in this condition, physically displacing PLN from SERCA2 might be beneficial in postinfarction, to limit the effects of chronic adrenergic signaling [ 98 ].…”

Mitochondrial a Kinase Anchor Proteins in Cardiovascular Health and Disease: A Review Article on Behalf of the Working Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology

“…Several AKAPs have been identified in adult cardiac myocytes and localized at distinct subcellular compartments, including the nucleus, mitochondria, endoplasmic reticulum, sarcomere and others [ 11 , 14 ]. Their roles have been intensely investigated under physiological and pathological conditions over the last few years and described extensively in recent reviews [ 15 , 16 ].…”