Cardiac cAMP-PKA Signaling Compartmentalization in Myocardial Infarction

Abstract

Under physiological conditions, cAMP signaling plays a key role in the regulation of cardiac function. Activation of this intracellular signaling pathway mirrors cardiomyocyte adaptation to various extracellular stimuli. Extracellular ligand binding to seven-transmembrane receptors (also known as GPCRs) with G proteins and adenylyl cyclases (ACs) modulate the intracellular cAMP content. Subsequently, this second messenger triggers activation of specific intracellular downstream effectors that ensure a proper cellular response. Therefore, it is essential for the cell to keep the cAMP signaling highly regulated in space and time. The temporal regulation depends on the activity of ACs and phosphodiesterases. By scaffolding key components of the cAMP signaling machinery, A-kinase anchoring proteins (AKAPs) coordinate both the spatial and temporal regulation. Myocardial infarction is one of the major causes of death in industrialized countries and is characterized by a prolonged cardiac ischemia. This leads to irreversible cardiomyocyte death and impairs cardiac function. Regardless of its causes, a chronic activation of cardiac cAMP signaling is established to compensate this loss. While this adaptation is primarily beneficial for contractile function, it turns out, in the long run, to be deleterious. This review compiles current knowledge about cardiac cAMP compartmentalization under physiological conditions and post-myocardial infarction when it appears to be profoundly impaired.

cAMP Compartmentalization in Cerebrovascular Endothelial Cells: New Therapeutic Opportunities in Alzheimer’s Disease

“…PKA is a serine/threonine kinase whose activation by cAMP results in the phosphorylation of a vast number of substrates [136]. It has been widely studied from a structural and functional point of view; moreover, its relationship with the origin and evolution of various diseases, such as myocardial infarction [144], cancer [145], and obesity [146], among many others, has been studied. Furthermore, PKA participates in gene transcription through phosphorylation of the cAMP-response element binding protein (CREB) at the level of the cell nucleus [73].…”

Dynamic Regulation of Cysteine Oxidation and Phosphorylation in Myocardial Ischemia–Reperfusion Injury

“…Cyclic AMP (cAMP)-dependent protein kinase (PKA) is also a mediator of cardioprotection ( Figure 1 ) [ 98 ]. PKA is activated by G-protein coupled receptors (e.g., β-adrenergic receptors) that stimulate adenylyl cyclase (AC), which produces the second messengers cAMP [ 99 ]. A-kinase-anchoring proteins (AKAPs) and phosphodiesterases (PDEs) compartmentalize cAMP and fine-tune the cAMP-mediated signaling cascade (as reviewed by Fischmeister et al (2006)) [ 100 ].…”

“…For instance, isoproterenol- and glucagon-like peptide-1 elicit cAMP production but activate unique pathways due to cAMP localization [ 101 , 102 ]. PKA exists as a heterotetramer with two regulatory domains—where AKAPs and cAMP bind—and two catalytic domains, which phosphorylate serine and threonine residues on substrate proteins [ 99 ]. Many of these PKA substrates are regulators of heart contraction.…”

“…Altogether, phosphorylation increases intracellular calcium and drives muscle contraction. Thorough reviews of PKA’s role in I/R injury were previously published (please see reviews by Colombe and Pidoux (2021), and Liu et al, (2021)), but we will present a few key studies here [ 98 , 99 ]. Previous reports have shown that β2-adrenergic stimulation protects the heart from acute I/R injury by stimulating cAMP and activating the PKA-Akt axis [ 103 ].…”

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“…The cAMP/PKA signaling pathway is one of the classical intracellular signaling transduction pathways, where the signal is first transmitted by G protein-coupled receptors to adenylate cyclase, so as to control the cAMP content and accordingly regulate the activity of PKA. The cAMP phosphorylates specific proteins to p-PKA through PKA, causing cellular effects [ 2 , 3 ]. The cyclic-AMP response element-binding protein (CREB) is a transcription factor located in the cellular nucleus and an effector of the cAMP signaling pathway, and it is involved in a variety of normal cellular physiological activities such as cellular proliferation, differentiation, and survival [ 4 ].…”