AKAP18δ Anchors and Regulates CaMKII Activity at Phospholamban-SERCA2 and RYR

Carlson, Cathrine R.; Aronsen, Jan Magnus; Bergan-Dahl, Anna; Moutty, Marie Christine; Lunde, Marianne; Lunde, Per; Jarstadmarken, Hilde; Wanichawan, Pimthanya; Pereira, Laëtitia; Kolstad, Terje R Selnes; Dalhus, Bjørn; Subramanian, Hariharan; Hille, Susanne; Christensen, Geir; Müller, Oliver; Nikolaev, Viacheslav O.; Bers, Donald M.; Sjaastad, Ivar; Shen, Xin Ming; Louch, William E.; Klussmann, Enno; Sejersted, Ole M.

doi:10.1161/circresaha.120.317976

Cited by 30 publications

(26 citation statements)

References 78 publications

(162 reference statements)

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“…In cardiomyocytes, PDE3A1 and PDE3A2 interact with a protein complex comprising AKAP 18 (A-kinase anchoring protein 18), PKA, CaMKIIδ (calmodulin kinase IIδ), SERCA2a (SR Ca 2+ -ATPase 2a), and PLN (phospholamban), which controls Ca 2+ reuptake into the SR and thereby relaxation. 21,38,39 Within the complex, cAMP-activated PKA phosphorylates PLN causing dissociation of PLN from SERCA2a releasing its inhibitory effect on SERCA2a. As a result, SERCA2a pumps Ca 2+ into the SR.…”

Section: Resultsmentioning

confidence: 99%

“…Functional enrichment analysis of DEGs revealed PDE3A-related involvement in protein folding, metabolism, and Ca 2+ regulation (Figures 7D-F). Because PDE3A plays a role in β-adrenergic signaling, Ca 2+ reuptake into the sarcoplasmic reticulum (SR) and thus relaxation of cardiomyocytes during diastole, 21,38,39 we focused on assessing components of the β-adrenergic system.…”

Section: Gene Expression Changes and Phospholamban Phosphorylation Is...mentioning

confidence: 99%

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Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage

et al. 2022

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Background: Phosphodiesterase 3A ( PDE3A ) gain-of-function mutations cause hypertension with brachydactyly (HTNB) and lead to stroke. Increased peripheral vascular resistance, rather than salt retention, is responsible. It is surprising that the few patients with HTNB examined so far did not develop cardiac hypertrophy or heart failure. We hypothesized that, in the heart, PDE3A mutations could be protective. Methods: We studied new patients. CRISPR-Cas9–engineered rat HTNB models were phenotyped by telemetric blood pressure measurements, echocardiography, microcomputed tomography, RNA-sequencing, and single nuclei RNA-sequencing. Human induced pluripotent stem cells carrying PDE3A mutations were established, differentiated to cardiomyocytes, and analyzed by Ca 2+ imaging. We used Förster resonance energy transfer and biochemical assays. Results: We identified a new PDE3A mutation in a family with HTNB. It maps to exon 13 encoding the enzyme’s catalytic domain. All hitherto identified HTNB PDE3A mutations cluster in exon 4 encoding a region N-terminally from the catalytic domain of the enzyme. The mutations were recapitulated in rat models. Both exon 4 and 13 mutations led to aberrant phosphorylation, hyperactivity, and increased PDE3A enzyme self-assembly. The left ventricles of our patients with HTNB and the rat models were normal despite preexisting hypertension. A catecholamine challenge elicited cardiac hypertrophy in HTNB rats only to the level of wild-type rats and improved the contractility of the mutant hearts, compared with wild-type rats. The β-adrenergic system, phosphodiesterase activity, and cAMP levels in the mutant hearts resembled wild-type hearts, whereas phospholamban phosphorylation was decreased in the mutants. In our induced pluripotent stem cell cardiomyocyte models, the PDE3A mutations caused adaptive changes of Ca 2+ cycling. RNA-sequencing and single nuclei RNA-sequencing identified differences in mRNA expression between wild-type and mutants, affecting, among others, metabolism and protein folding. Conclusions: Although in vascular smooth muscle, PDE3A mutations cause hypertension, they confer protection against hypertension-induced cardiac damage in hearts. Nonselective PDE3A inhibition is a final, short-term option in heart failure treatment to increase cardiac cAMP and improve contractility. Our data argue that mimicking the effect of PDE3A mutations in the heart rather than nonselective PDE3 inhibition is cardioprotective in the long term. Our findings could facilitate the search for new treatments to prevent hypertension-induced cardiac damage.

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Section: Resultsmentioning

confidence: 99%

Section: Gene Expression Changes and Phospholamban Phosphorylation Is...mentioning

confidence: 99%

Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage

et al. 2022

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“…At the cardiomyocyte SR, SERCA is anchored to AKAP18δ forming a domain with PKA, PDE3A1, PDE4D, SERCA2, PLN, CaM, and CaMKIIδ [ 73 , 74 ]. PKA-mediated phosphorylation of PLN results in the dissociation of PLN from SERCA2, allowing diastolic SR calcium reuptake and myofilament relaxation [ 60 ].…”

Section: Regulation Of Cardiac Function By Camp Nanodomainsmentioning

confidence: 99%

Regulation of cardiac function by cAMP nanodomains

Folkmanaite

Zaccolo

2023

Bioscience Reports

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Cyclic adenosine monophosphate (cAMP) is a diffusible intracellular second messenger that plays a key role in the regulation of cardiac function. In response to the release of catecholamines from sympathetic terminals, cAMP modulates heart rate and the strength of contraction and ease of relaxation of each heartbeat. At the same time, cAMP is involved in the response to a multitude of other hormones and neurotransmitters. A sophisticated network of regulatory mechanisms controls the temporal and spatial propagation of cAMP, resulting in the generation of signaling nanodomains that enable the second messenger to match each extracellular stimulus with the appropriate cellular response. Multiple proteins contribute to this spatio-temporal regulation, including the cAMP-hydrolyzing phosphodiesterases. By breaking down cAMP to a different extent at different locations, these enzymes generate subcellular cAMP gradients. As a result, only a subset of the downstream effectors is activated and a specific response is executed. Dysregulation of cAMP compartmentalization has been observed in cardiovascular diseases, highlighting the importance of appropriate control of local cAMP signaling. Current research is unveiling the molecular organization underpinning cAMP compartmentalization, providing original insight into the physiology of cardiac myocytes and the alteration associated with disease, with the potential to uncover novel therapeutic targets. Here we present an overview of the mechanisms that are currently understood to be involved in generating cAMP nanodomains and we highlight the questions that remain to be answered.

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“…Because the composition of a cluster (e.g., number of Timothy syndrome versus wild-type channels) is stochastic, it is a likely source of Ca 2+ -entry noise. The composition of a cluster and the interaction and phosphorylation of a channel with a kinase (e.g., PKA, Ca 2+ /calmodulin kinase II, PKC⍺)—even if bound to an anchoring protein ( Carlson et al, 2022 ; Craske et al, 2005 ; Smith et al, 2017 ; Tajada et al, 2017 )—are also likely stochastic, and thus are additional sources of Ca 2+ -entry noise.…”

Section: Fluctuations In Ca V 12 Conductance Durin...mentioning

confidence: 99%

Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling

Guarina

Moghbel

Pourhosseinzadeh

et al. 2022

Journal of General Physiology

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Each heartbeat begins with the generation of an action potential in pacemaking cells in the sinoatrial node. This signal triggers contraction of cardiac muscle through a process termed excitation–contraction (EC) coupling. EC coupling is initiated in dyadic structures of cardiac myocytes, where ryanodine receptors in the junctional sarcoplasmic reticulum come into close apposition with clusters of CaV1.2 channels in invaginations of the sarcolemma. Cooperative activation of CaV1.2 channels within these clusters causes a local increase in intracellular Ca2+ that activates the juxtaposed ryanodine receptors. A salient feature of healthy cardiac function is the reliable and precise beat-to-beat pacemaking and amplitude of Ca2+ transients during EC coupling. In this review, we discuss recent discoveries suggesting that the exquisite reproducibility of this system emerges, paradoxically, from high variability at subcellular, cellular, and network levels. This variability is attributable to stochastic fluctuations in ion channel trafficking, clustering, and gating, as well as dyadic structure, which increase intracellular Ca2+ variance during EC coupling. Although the effects of these large, local fluctuations in function and organization are sometimes negligible at the macroscopic level owing to spatial–temporal summation within and across cells in the tissue, recent work suggests that the “noisiness” of these intracellular Ca2+ events may either enhance or counterintuitively reduce variability in a context-dependent manner. Indeed, these noisy events may represent distinct regulatory features in the tuning of cardiac contractility. Collectively, these observations support the importance of incorporating experimentally determined values of Ca2+ variance in all EC coupling models. The high reproducibility of cardiac contraction is a paradoxical outcome of high Ca2+ signaling variability at subcellular, cellular, and network levels caused by stochastic fluctuations in multiple processes in time and space. This underlying stochasticity, which counterintuitively manifests as reliable, consistent Ca2+ transients during EC coupling, also allows for rapid changes in cardiac rhythmicity and contractility in health and disease.

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AKAP18δ Anchors and Regulates CaMKII Activity at Phospholamban-SERCA2 and RYR

Cited by 30 publications

References 78 publications

Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage

Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage

Regulation of cardiac function by cAMP nanodomains

Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling

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