Plasma Membrane Calcium Pump (PMCA4)-Neuronal Nitric-oxide Synthase Complex Regulates Cardiac Contractility through Modulation of a Compartmentalized Cyclic Nucleotide Microdomain

被引：59

作者：

Mohamed, Tamer M. A. ^{[1
,2
]}

Oceandy, Delvac ^{[1
]}

Zi, Min ^{[1
]}

Prehar, Sukhpal ^{[1
]}

Alatwi, Nasser ^{[1
]}

Wang, Yanwen ^{[1
]}

Shaheen, Mohamed A. ^{[1
]}

Abou-Leisa, Riham ^{[1
]}

Schelcher, Celine ^{[1
]}

Hegab, Zeinab ^{[1
]}

Baudoin, Florence ^{[1
]}

Emerson, Michael ^{[3
]}

Mamas, Mamas ^{[1
]}

Di Benedetto, Giulietta ^{[4
]}

Zaccolo, Manuela ^{[5
]}

Lei, Ming ^{[1
]}

Cartwright, Elizabeth J. ^{[1
]}

Neyses, Ludwig ^{[1
]}

机构：

[1] Univ Manchester, Cardiovasc Med Res Grp, Manchester Acad Hlth Sci Ctr, Manchester M13 9PT, Lancs, England

[2] Zagazig Univ, Fac Pharm, Dept Biochem, Zagazig 44519, Egypt

[3] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Platelet Biol Grp, London SW7 2AZ, England

[4] Venetian Inst Mol Med, I-35100 Padua, Italy

[5] Univ Glasgow, Inst Neurosci & Psychol, Glasgow G12 8QQ, Lanark, Scotland

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2011年 / 286卷 / 48期

基金：

英国医学研究理事会;

关键词：

HEART; CA2+; OVEREXPRESSION; TRANSPORT; ATPASE; HEALTH; SIGNAL; CAMP;

D O I：

10.1074/jbc.M111.290411

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Ca2+/calmodulinde-pendent ATPase 4 (PMCA4) is a regulator of neuronal nitricoxide 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.

引用

页码：41520 / 41529

页数：10

共 45 条

[41] The sarcolemmal calcium pump, α-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex [J].