Polymorphisms/Mutations in A-Kinase Anchoring Proteins (AKAPs): Role in the Cardiovascular System

Abstract

A-kinase anchoring proteins (AKAPs) belong to a family of scaffolding proteins that bind to protein kinase A (PKA) by definition and a variety of crucial proteins, including kinases, phosphatases, and phosphodiesterases. By scaffolding these proteins together, AKAPs build a “signalosome” at specific subcellular locations and compartmentalize PKA signaling. Thus, AKAPs are important for signal transduction after upstream activation of receptors ensuring accuracy and precision of intracellular PKA-dependent signaling pathways. Since their discovery in the 1980s, AKAPs have been studied extensively in the heart and have been proven essential in mediating cyclic adenosine monophosphate (cAMP)-PKA signaling. Although expression of AKAPs in the heart is very low, cardiac-specific knock-outs of several AKAPs have a noteworthy cardiac phenotype. Moreover, single nucleotide polymorphisms and genetic mutations in crucial cardiac proteins play a substantial role in the pathophysiology of cardiovascular diseases (CVDs). Despite the significant role of AKAPs in the cardiovascular system, a limited amount of research has focused on the role of genetic polymorphisms and/or mutations in AKAPs in increasing the risk of CVDs. This review attempts to overview the available literature on the polymorphisms/mutations in AKAPs and their effects on human health with a special focus on CVDs.

Histone deacetylase inhibition reduces ventral tegmental area dopamine neuronal hyperexcitability involving AKAP150 signaling following maternal deprivation in juvenile male rats

“…Specifically, AKAP150 can modulate neuronal excitability not only through synaptic transmission, but also by direct interaction and modulation of ion channel activity and trafficking of postsynaptic ion channels that regulate intrinsic neuronal excitability (Lin et al, 2011; Murphy et al, 2014; Welch, Jones, & Scott, 2010). Interestingly, individuals carrying AKAP5 polymorphisms show altered emotional processing and behavioral responses including aggression, expression of anger, and impulsivity associated with alterations in function in limbic regions (Richter et al, 2011, 2013; Suryavanshi, Jadhav, & McConnell, 2018). Moreover, copy number variations in AKAP5 have been found in DNA samples of schizophrenia patients but not control subjects (Sutrala et al, 2007), suggesting the possible involvement of AKAP5 in the pathogenesis of schizophrenia, a neurodevelopmental disorder also linked to DA dysfunction, ELS, and high rates of addiction (Scheller‐Gilkey, Moynes, Cooper, Kant, & Miller, 2004; Scheller‐Gilkey, Thomas, Woolwine, & Miller, 2002; Winklbaur, Ebner, Sachs, Thau, & Fischer, 2006).…”

Single nucleotide polymorphisms alter kinase anchoring and the subcellular targeting of A-kinase anchoring proteins

“…Genome-wide association surveys have identified point mutations and SNPs in genes encoding AKAPs that are linked to a variety of neurological and cardiac diseases (reviewed in ref. 14). The National Center for Biotechnology Information (NCBI) SNP (https://www.ncbi.nlm.…”

“…This "signaling island" concept radically changes the view of how AKAP complexes operate and indicates that protein phosphorylation is more regionally confined than previously appreciated (22). As our understanding of how signaling enzyme complexes operate becomes more refined, it is evident that perturbation of AKAP-PKA interactions is linked to disease (11,14). Scrutiny of big datasets has uncovered genetic variation in AKAPs that correlate with susceptibility to diseases, such as schizophrenia, Alzheimer's, certain cardiac arrhythmias, and the onset of febrile seizures (12,14,25,26).…”

“…As our understanding of how signaling enzyme complexes operate becomes more refined, it is evident that perturbation of AKAP-PKA interactions is linked to disease (11,14). Scrutiny of big datasets has uncovered genetic variation in AKAPs that correlate with susceptibility to diseases, such as schizophrenia, Alzheimer's, certain cardiac arrhythmias, and the onset of febrile seizures (12,14,25,26). In this report we systematically investigate the properties of polymorphic variants in AKAPs that elicit single amino acid changes in RII-anchoring helices.…”

“…These organizational elements ensure that signals are transmitted to precise sites within the cell (11). Hence, genetic lesions that disrupt protein kinase anchoring have been linked to various pathological responses and may represent untapped therapeutic targets (12)(13)(14).…”