دورية أكاديمية
Plasma membrane calcium pump (PMCA4)-neuronal nitric-oxide synthase complex regulates cardiac contractility through modulation of a compartmentalized cyclic nucleotide microdomain.
| العنوان: | Plasma membrane calcium pump (PMCA4)-neuronal nitric-oxide synthase complex regulates cardiac contractility through modulation of a compartmentalized cyclic nucleotide microdomain. |
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| المؤلفون: | Mohamed, T, Oceandy, D, Zi, M, Prehar, S, Alatwi, N, Wang, Y, Shaheen, M, Abou-Leisa, R, Schelcher, C, Hegab, Z, Baudoin, F, Emerson, M, Mamas, M, Di Benedetto, G, Zaccolo, M, Lei, M, Cartwright, E, Neyses, L |
| سنة النشر: | 2016 |
| المجموعة: | Oxford University Research Archive (ORA) |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://ora.ox.ac.uk/objects/uuid:e97a6445-fe78-49d1-ae12-26e63eeed06eTest; https://doi.org/10.1074/jbc.m111.290411Test |
| DOI: | 10.1074/jbc.m111.290411 |
| الإتاحة: | https://doi.org/10.1074/jbc.m111.290411Test https://ora.ox.ac.uk/objects/uuid:e97a6445-fe78-49d1-ae12-26e63eeed06eTest |
| حقوق: | info:eu-repo/semantics/embargoedAccess |
| رقم الانضمام: | edsbas.C16B9A7 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1074/jbc.m111.290411 |
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