ArticleThe Journal of biological chemistry2011
Plasma membrane calcium pump (PMCA4)-neuronal nitric-oxide synthase complex regulates cardiac contractility through modulation of a compartmentalized cyclic nucleotide microdomain.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 79 citations in OpenAlex.
- Integrating network pharmacology and transcriptomics to reveal the therapeutic effect of Long Mu Ning Xin Decoction on attention-deficit/hyperactivity disorder by regulating cAMP and PI3K/AKT pathways.Frontiers in pharmacology · 2026Article
- Plasma membrane calcium ATPases and cerebellar pathology: what's the role in the ataxia?Biology direct · 2025Review
- CaAnimal cells and systems · 2024Review
- Genetic variations in human ATP2B4 gene alter Plasmodium falciparum in vitro growth in RBCs from Gambian adults.Malaria journal · 2023Article
- The ataxia-linked E1081Q mutation affects the sub-plasma membrane CaCell death & disease · 2022Article
- Structure, Function and Regulation of the Plasma Membrane Calcium Pump in Health and Disease.International journal of molecular sciences · 2022Review
- Measuring Spatiotemporal cAMP Dynamics Within an Endogenous Signaling Compartment Using FluoSTEP-ICUE.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Compartmentalized cAMP signaling in cardiac ventricular myocytes.Cellular signalling · 2022Review
- Mechanisms of cAMP compartmentation in cardiac myocytes: experimental and computational approaches to understanding.The Journal of physiology · 2021Review
- PMCA4 inhibition does not affect cardiac remodelling following myocardial infarction, but may reduce susceptibility to arrhythmia.Scientific reports · 2021Article
- Plasma Membrane CaFrontiers in cellular neuroscience · 2021Article
- Primary Active CaCold Spring Harbor perspectives in biology · 2020Review
- The Control of Diastolic Calcium in the Heart: Basic Mechanisms and Functional Implications.Circulation research · 2020Review
- Neuronal nitric oxide synthase regulation of calcium cycling in ventricular cardiomyocytes is independent of CaPflugers Archiv : European journal of physiology · 2020Article
- Acute inhibition of PMCA4, but not global ablation, reduces blood pressure and arterial contractility via a nNOS-dependent mechanism.Journal of cellular and molecular medicine · 2018Article
- Advanced glycation end products reduce the calcium transient in cardiomyocytes by increasing production of reactive oxygen species and nitric oxide.FEBS open bio · 2017Article
- Why Calcium? How Calcium Became the Best Communicator.The Journal of biological chemistry · 2016Review
- The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy.Nature communications · 2016Article
- Article
- Neuronal nitric oxide synthase-dependent amelioration of diastolic dysfunction in rats with chronic renocardiac syndrome.Cardiorenal medicine · 2015Article
Corrections and comments
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Authors and funding
18 authors at 6 institutions in 3 countries.
Funding
Abstract
Identification of the signaling pathways that regulate cyclic nucleotide microdomains is essential to our understanding of cardiac physiology and pathophysiology. Although there is growing evidence that the plasma membrane Ca(2+)/calmodulin-dependent ATPase 4 (PMCA4) is a regulator of neuronal nitric-oxide synthase, the physiological consequence of this regulation is unclear. We therefore tested the hypothesis that PMCA4 has a key structural role in tethering neuronal nitric-oxide synthase to a highly compartmentalized domain in the cardiac cell membrane. This structural role has functional consequences on cAMP and cGMP signaling in a PMCA4-governed microdomain, which ultimately regulates cardiac contractility. In vivo contractility and calcium amplitude were increased in PMCA4 knock-out animals (PMCA4(-/-)) with no change in diastolic relaxation or the rate of calcium decay, showing that PMCA4 has a function distinct from beat-to-beat calcium transport. Surprisingly, in PMCA4(-/-), over 36% of membrane-associated neuronal nitric-oxide synthase (nNOS) protein and activity was delocalized to the cytosol with no change in total nNOS protein, resulting in a significant decrease in microdomain cGMP, which in turn led to a significant elevation in local cAMP levels through a decrease in PDE2 activity (measured by FRET-based sensors). This resulted in increased L-type calcium channel activity and ryanodine receptor phosphorylation and hence increased contractility. In the heart, in addition to subsarcolemmal calcium transport, PMCA4 acts as a structural molecule that maintains the spatial and functional integrity of the nNOS signaling complex in a defined microdomain. This has profound consequences for the regulation of local cyclic nucleotide and hence cardiac β-adrenergic signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.