title: Phosphodiesterase type 3A regulates basal myocardial contractility through interacting with sarcoplasmic reticulum calcium ATPase type 2a signaling complexes in mouse heart.
abstract: BACKGROUND
  cAMP is an important regulator of myocardial function, and regulation of cAMP hydrolysis by cyclic nucleotide phosphodiesterases (PDEs) is a critical determinant of the amplitude, duration, and compartmentation of cAMP-mediated signaling. The role of different PDE isozymes, particularly PDE3A vs PDE3B, in the regulation of heart function remains unclear.
  
  
  OBJECTIVE
  To determine the relative contribution of PDE3A vs PDE3B isozymes in the regulation of heart function and to dissect the molecular basis for this regulation.
  
  
  RESULTS
  Compared with wild-type littermates, cardiac contractility and relaxation were enhanced in isolated hearts from PDE3A(-/-), but not PDE3B(-/-), mice. Furthermore, PDE3 inhibition had no effect on PDE3A(-/-) hearts but increased contractility in wild-type (as expected) and PDE3B(-/-) hearts to levels indistinguishable from PDE3A(-/-). The enhanced contractility in PDE3A(-/-) hearts was associated with cAMP-dependent elevations in Ca(2+) transient amplitudes and increased sarcoplasmic reticulum (SR) Ca(2+) content, without changes in L-type Ca(2+) currents of cardiomyocytes, as well as with increased SR Ca(2+)-ATPase type 2a activity, SR Ca(2+) uptake rates, and phospholamban phosphorylation in SR fractions. Consistent with these observations, PDE3 activity was reduced ≈8-fold in SR fractions from PDE3A(-/-) hearts. Coimmunoprecipitation experiments further revealed that PDE3A associates with both SR calcium ATPase type 2a and phospholamban in a complex that also contains A-kinase anchoring protein-18, protein kinase type A-RII, and protein phosphatase type 2A.
  
  
  CONCLUSIONS
  Our data support the conclusion that PDE3A is the primary PDE3 isozyme modulating basal contractility and SR Ca(2+) content by regulating cAMP in microdomains containing macromolecular complexes of SR calcium ATPase type 2a-phospholamban-PDE3A.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sanja
authors.initials: S
authors.lastname: Beca
authors.forename: Faiyaz
authors.initials: F
authors.lastname: Ahmad
authors.forename: Weixing
authors.initials: W
authors.lastname: Shen
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Samy
authors.initials: S
authors.lastname: Makary
authors.forename: Nazari
authors.initials: N
authors.lastname: Polidovitch
authors.forename: Junhui
authors.initials: J
authors.lastname: Sun
authors.forename: Steven
authors.initials: S
authors.lastname: Hockman
authors.forename: Youn Wook
authors.initials: YW
authors.lastname: Chung
authors.forename: Matthew
authors.initials: M
authors.lastname: Movsesian
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
authors.forename: Vincent
authors.initials: V
authors.lastname: Manganiello
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006321:Heart / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517289:Pde3a protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse