Reference : Plasma membrane calcium pump (PMCA4)-neuronal nitric-oxide synthase complex regulates...
Scientific journals : Article
Human health sciences : Cardiovascular & respiratory systems
Plasma membrane calcium pump (PMCA4)-neuronal nitric-oxide synthase complex regulates cardiac contractility through modulation of a compartmentalized cyclic nucleotide microdomain.
Mohamed, Tamer M. A. [> >]
Oceandy, Delvac [> >]
Zi, Min [> >]
Prehar, Sukhpal [> >]
Alatwi, Nasser [> >]
Wang, Yanwen [> >]
Shaheen, Mohamed A. [> >]
Abou-Leisa, Riham [> >]
Schelcher, Celine [> >]
Hegab, Zeinab [> >]
Baudoin, Florence [> >]
Emerson, Michael [> >]
Mamas, Mamas [> >]
Di Benedetto, Giulietta [> >]
Zaccolo, Manuela [> >]
Lei, Ming [> >]
Cartwright, Elizabeth J. [> >]
Neyses, Ludwig mailto [University of Luxembourg > Research Office]
The Journal of biological chemistry
Yes (verified by ORBilu)
United States
[en] Animals ; Calcium/metabolism ; Cyclic AMP/metabolism ; Cyclic GMP/genetics/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 2/genetics/metabolism ; Ion Transport/physiology ; Membrane Microdomains/enzymology/genetics ; Mice ; Mice, Knockout ; Multienzyme Complexes/genetics/metabolism ; Muscle Proteins/genetics/metabolism ; Myocardial Contraction/physiology ; Myocytes, Cardiac/enzymology ; Nitric Oxide Synthase Type I/genetics/metabolism ; Plasma Membrane Calcium-Transporting ATPases/genetics/metabolism ; Signal Transduction/physiology
[en] 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 beta-adrenergic signaling.

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