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.

Keywords: A-kinase anchoring protein; cAMP signaling; cardiomyocytes; heart; myocardial infarction; phosphodiesterases; protein kinase A.

Figure 1

β-Adrenergic Receptor and cAMP signaling pathways in the heart. β-Adrenergic Receptor (β-AR) activates adenylyl cyclase and generates pools of cAMP. cAMP (dark red-filled circles) has effects on a range of down effectors encompassing: PKA, Epac, POPDC, hyperpolarization activated cyclic nucleotide (HCN) channel and phosphodiesterases (PDEs). PKA activation leads to phosphorylation (P in pink circles) of specific substrates regulating Ca²⁺ flux and cardiac excitation–contraction coupling (CEC) (e.g., PLB, Ca_V1.2 (LTCC), RyR2, TnI, MyBPC). Cyclic AMP binding to Epac favors exchange of RAP-GDP into RAP-GTP, which activates phosphorylation by PKC and CaMK2 (P in yellow and purple circles, respectively). Activated Epac regulates gene transcription. Cyclic AMP binding to HCN channels triggers ion flux (Na⁺, K⁺) and hyperpolarization. Local concentration of cAMP gradient is limited by phosphodiesterases (PDEs), which hydrolyze cyclic nucleotide in inactive 5′-AMP, leading to termination of signaling.

Figure 2

Cardiac AKAPs and cAMP signaling compartmentalization in myocardial infarction (MI). (A) AKAP1 coordinates at the mitochondria a cardioprotective macrocomplex that mediates phosphorylation of Drp1 by anchored PKA, which inhibits mitochondrial fission and leads to cell survival (left). This process is counterbalanced by CaN recruitment on AKAP1 signaling complex, which, in contrast, favors Drp1 dephosphorylation and mitochondrial fragmentation (right). (B) Role of cardiac AKAP5 under physiological conditions and after MI. In cardiomyocytes, AKAP5-anchored PKA mediates direct AC5 and AC6 phosphorylation to inhibit AC activity and cAMP production (top left). AKAP5 brings PKA in proximity to LTCC, which regulates Ca²⁺ entry (bottom left). AKAP5 anchors CaN and participates in NFATc3 activation, which down-regulates K_v channel expression level, reduces I_Kv, prolongs action potential duration and favors arrhythmia susceptibility post-MI (right). (C) Role of cardiac AKAP6 under physiological conditions and after MI. Activated AC5 produces a pool of cAMP that mobilizes AKAP6-anchored PKA. PKA phosphorylates AC5 and AKAP6-anchored PDE4D that, respectively, inhibit AC5-dependent cAMP production and trigger local cAMP degradation by PDE4D (left). Under physiological conditions, AKAP6 mediates HIF1-α ubiquitination and degradation, while hypoxia inhibits this process and leads to HIF1-α accumulation. HIF1-α complexes with HIF1-β and initiates transcription of pro-survival genes to favor cell survival under ischemic stress (right). (D) Cardiac AKAP10 and AKAP12 under physiological conditions. In the heart, AKAP10 distributes to the mitochondria, in the cytoplasm (with small GTPases Rab4 and Rab11) and at the plasmalemma (associated with Na/H exchanger (NHERF)). AKAP12 favors β-AR phosphorylation and triggers GPCR desensitization/resensitization cycling. In the heart, angiotensin II (AngII) activates cardiac TGFβ1 pathways, which favors oxidative stress, apoptosis and fibrosis. AKAP12 inhibits deleterious AngII and the TGFβ1 pathway and exhibits cardioprotective properties. AKAP: A-kinase anchoring protein; HIF1α: Hypoxia Induced Factor-1α; CaN: calcineurin; PDE4: phosphodiesterase 4; AC5/6: adenylyl cyclase 5/6; β-AR: β-Adrenergic Receptor.

Figure 3

Cardiac cAMP-PDEs. (A) Structure of major cardiac cAMP-PDEs. PDEs exhibit a conserved C-terminal catalytic domain and a variable N-terminal regulatory domain. Kinase-dependent phosphorylation sites are indicated as circled P (light pink for PKA, yellow for PKC, purple for CaMK2, dark pink for PKB and mixed with light pink and purple for PKA and CaMK2). CaM: calmodulin binding domain; GAF: GAF (i.e., cGMP-dependent PDE, Anabaena adenylyl cyclases and E. Coli FhlA) domain; UCR: upstream conserved region; PAS: Per-Arnt-Sim domain; and PDE: phosphodiesterase. (B) Scheme of major cardiac cAMP-PDE compartmentalization. GPCR: G protein-coupled receptor; β-AR: β-Adrenergic Receptor; TnI: troponin I; RyR2: Ryanodine receptor-2; Epac: Exchange Protein Activated by cAMP, PKA: Protein Kinase-A; SERCA2: Sarco/Endoplasmic Reticulum Ca²⁺-ATPase; PLB: Phospholamban; AKAP: A-kinase anchoring protein.