The Large Isoforms of A-Kinase Anchoring Protein 18 Mediate the Phosphorylation of Inhibitor-1 by Protein Kinase A and the Inhibition of Protein Phosphatase 1 Activity

Singh, Avtar; Redden, John M.; Kapiloff, Michael S.; Dodge‐Kafka, Kimberly L.

doi:10.1124/mol.110.065425

Cited by 36 publications

(33 citation statements)

References 24 publications

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“…Published reports propose a model where AKAP7γ/δ coordinates a multimolecular complex including PKA, inhibitor-1, and protein phosphatase 1 in the regulation of PLN (16,17). We tested this model by stimulating isolated adult ventricular cardiomyocytes in vitro with increasing concentrations of ISO (0.1-1,000 nM) and analyzing phosphorylated PLN by immunoblot.…”

Section: Resultsmentioning

confidence: 99%

“…AKAP7δ in rat heart binds to PLN and coordinates its phosphorylation by PKA. A recent study reported that AKAP7δ in rat heart also coordinates PKA phosphorylation of inhibitor-1 (17), which in turn inhibits protein phosphatase 1 (18). Because protein phosphatase 1 is the major phosphatase responsible for dephosphorylating PLN (18,19), this suggests that the long isoforms of AKAP7 may coordinate both phosphorylation and dephosphorylation of PLN.…”

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confidence: 99%

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Cardiomyocytes from AKAP7 knockout mice respond normally to adrenergic stimulation

Jones¹,

Brunet²,

Gilbert³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Protein kinase A (PKA) is activated during sympathetic stimulation of the heart and phosphorylates key proteins involved in cardiac Ca 2+ handling, including the L-type Ca 2+ channel (Ca V 1.2) and phospholamban (PLN). This results in acceleration and amplification of the beat-to-beat changes in cytosolic Ca 2+ in cardiomyocytes and, in turn, an increased rate and force of contraction. PKA is held in proximity to its substrates by protein scaffolds called A kinase anchoring proteins (AKAPs). It has been suggested that the short and long isoforms of AKAP7 (also called AKAP15/18) localize PKA in complexes with Ca V 1.2 and PLN, respectively. We generated an AKAP7 KO mouse in which all isoforms were deleted and tested whether Ca 2+ current, intracellular Ca 2+ concentration, or Ca 2+ reuptake were impaired in isolated adult ventricular cardiomyocytes following stimulation with the β-adrenergic agonist isoproterenol. KO T he key determinants of cardiac output-the force of contraction and rate of relaxation-are rooted in the amplitude and kinetics of Ca 2+ transients that occur in individual cardiomyocytes. Adrenergic stimulation initiates cAMP-dependent signaling pathways that activate PKA leading to phosphorylation of numerous proteins that are critical for Ca 2+ entry, release, and reuptake, as well as sarcomeric proteins more closely associated with contraction, such as myosin-binding protein C and troponin I. This phosphorylation amplifies Ca 2+ influx through voltagegated Ca 2+ channels (Ca V 1.2 in the ventricle) and the corresponding increase in Ca 2+ -induced Ca 2+ release from the sarcoplasmic reticulum (SR) through ryanodine receptors augments contractility. Equally important is the enhanced removal of Ca 2+ from the cytosol that allows the heart to relax more quickly during diastole, which is accomplished primarily by phosphorylating phospholamban (PLN), which in turn relieves PLN inhibition of the sarcoplasmic reticulum Ca 2+ ATPase (SERCA). Distinct, localized actions of PKA are coordinated in two ways: (i) cAMP production and hydrolysis are restricted by the subcellular localization of cyclases and phosphodiesterases, respectively, and (ii) PKA is directed to specific subcellular sites by binding to an assortment of protein scaffolds known as A kinase anchoring proteins (AKAPs) (1). By directing PKA to specific subcellular sites, AKAPs determine not only the specificity of protein phosphorylation, but also the speed with which these systems respond to adrenergic stimulation. Some AKAPs are implicated in clinically relevant cardiac signaling events (2-4). For example, regulation of potassium channel current in the heart depends on formation of complexes containing AKAP9 (yotiao), PKA, and the I Ks potassium channel α subunit (KCNQ1); an inherited single point mutation in AKAP9 impairs AKAP9-KCNQ1 interaction and ultimately leads to long QT syndrome (4).AKAP7 is expressed as a family of alternatively spliced anchoring proteins that bind all isoforms of PKA regulatory subunit, albeit with different aff...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Cardiomyocytes from AKAP7 knockout mice respond normally to adrenergic stimulation

Jones¹,

Brunet²,

Gilbert³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…AKAP7 interacts indirectly with calcineurin by providing a scaffold for the protein phosphatase inhibitor 1 (I-1), a calcineurin substrate that controls the activity of the protein phosphatase 1 (PP1) [183]. Phosphorylation of I-1 at Thr35 by PKA induces selective inhibition of PP1 [184].…”

Section: Calcineurin Substrates Relevant To Cardiovascular Healthmentioning

confidence: 99%

Calcineurin signaling in the heart: The importance of time and place

Parra

Rothermel

2017

Journal of Molecular and Cellular Cardiology

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The calcium-activated protein phosphatase, calcineurin, lies at the intersection of protein phosphorylation and calcium signaling cascades, where it provides an essential nodal point for coordination between these two fundamental modes of intracellular communication. In excitatory cells, such as neurons and cardiomyocytes, that experience rapid and frequent changes in cytoplasmic calcium, calcineurin protein levels are exceptionally high, suggesting that these cells require high levels of calcineurin activity. Yet, it is widely recognized that excessive activation of calcineurin in the heart contributes to pathological hypertrophic remodeling and the progression to failure. How does a calcium activated enzyme function in the calcium-rich environment of the continuously contracting heart without pathological consequences? This review will discuss the wide range of calcineurin substrates relevant to cardiovascular health and the mechanisms calcineurin uses to find and act on appropriate substrates in the appropriate location while potentially avoiding others. Fundamental differences in calcineurin signaling in neonatal verses adult cardiomyocytes will be addressed as well as the importance of maintaining heterogeneity in calcineurin activity across the myocardium. Finally, we will discuss how circadian oscillations in calcineurin activity may facilitate integration with other essential but conflicting processes, allowing a healthy heart to reap the benefits of calcineurin signaling while avoiding the detrimental consequences of sustained calcineurin activity that can culminate in heart failure.

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“…Accordingly, the silencing of AKAP18␦ or the disruption of the interaction between AKAP18␦ and PLB in cardiomyocytes was shown to impair ␤-AR-induced Ca 2ϩ reuptake from the cytosol into the sarcoplasmic reticulum and to inhibit cardiomyocyte relaxation (68). Interestingly, recent findings indicate that AKAP18␦ also recruits protein phosphatase 1 (PP1) and its negative regulator inhibitor-1 (I-1), favoring PKA-mediated phosphorylation of I-1 and the consequent inhibition of PP1 activity (105). Knowing that PP1 can inhibit SERCA2 activity via PLB dephosphorylation, it is plausible that AKAP18␦, by facilitating I-1-dependent PP1 regulation, might further promote cardiomyocyte relaxation.…”

Section: Akaps and Ca 2ϩ Cyclingmentioning

confidence: 99%

A-kinase anchoring proteins: scaffolding proteins in the heart

Diviani

Dodge‐Kafka

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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101

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The pleiotropic cyclic nucleotide cAMP is the primary second messenger responsible for autonomic regulation of cardiac inotropy, chronotropy, and lusitropy. Under conditions of prolonged catecholaminergic stimulation, cAMP also contributes to the induction of both cardiac myocyte hypertrophy and apoptosis. The formation of localized, multiprotein complexes that contain different combinations of cAMP effectors and regulatory enzymes provides the architectural infrastructure for the specialization of the cAMP signaling network. Scaffolds that bind protein kinase A are called “A-kinase anchoring proteins” (AKAPs). In this review, we discuss recent advances in our understanding of how PKA is compartmentalized within the cardiac myocyte by AKAPs and how AKAP complexes modulate cardiac function in both health and disease.

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The Large Isoforms of A-Kinase Anchoring Protein 18 Mediate the Phosphorylation of Inhibitor-1 by Protein Kinase A and the Inhibition of Protein Phosphatase 1 Activity

Cited by 36 publications

References 24 publications

Cardiomyocytes from AKAP7 knockout mice respond normally to adrenergic stimulation

Cardiomyocytes from AKAP7 knockout mice respond normally to adrenergic stimulation

Calcineurin signaling in the heart: The importance of time and place

A-kinase anchoring proteins: scaffolding proteins in the heart

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