title: Identifying a role of the actin capping protein CapZ in β-adrenergic receptor signalling.
abstract: OBJECTIVE
  β-Adrenergic receptor activation increases myocardial contractility, in part through protein kinase A (PKA)-dependent modification of cardiac myofilaments. PKA regulation of cardiac myofilaments is contingent influenced by protein kinase C (PKC) phosphorylation of troponin I (TnI). Reductions in the cardiac Z-disc protein CapZ attenuate PKC regulation of myofilament activation. We hypothesized that CapZ-deficient transgenic mouse hearts respond poorly to β-adrenergic receptor activation, as a result of impaired PKC activation.
  
  
  METHODS
  Wild-type and CapZ-deficient transgenic mice were treated with the β-adrenergic receptor agonist isoproterenol (ISO) and whole heart function assessed by echocardiography. Cardiac myofilaments were isolated post-ISO treatment and subjected to an actomyosin MgATPase assay and protein phosphorylation gels.
  
  
  RESULTS
  CapZ-deficient transgenic mouse hearts exhibited increased contractility and myofilament calcium sensitivity at baseline, as compared to wild-type mice. In wild-type mice, ISO increased myocardial contractility and decreased myofilament calcium sensitivity, along with an increase in TnI phosphorylation. CapZ-deficient transgenic mice responded to ISO treatment, and myocardial functional differences between transgenic and wild-type mice were abolished. ISO-dependent changes in myofilament activation in transgenic mice were similar to those observed in wild-type. TnI phosphorylation was similarly increased in wild-type and transgenic mice following ISO treatment, while CapZ-deficient transgenic mouse myofilaments also exhibited increased myosin-binding protein C phosphorylation. Differences in myofilament protein phosphorylation patterns suggest the intracellular mechanisms utilized by β-adrenergic receptor activation are different than that seen in wild-type hearts.
  
  
  CONCLUSIONS
  These data further support the concept that the cardiac Z-disc protein is a regulator of myofilament function and intracellular signalling transduction.
authors.affiliation: Cardiovascular Research Group, Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Gaikis
authors.forename: D
authors.initials: D
authors.lastname: Stewart
authors.forename: R
authors.initials: R
authors.lastname: Johnson
authors.forename: W G
authors.initials: WG
authors.lastname: Pyle
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D051347:CapZ Actin Capping Protein / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D009210:Myofibrils / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013318:Stroke Volume / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D051347:CapZ Actin Capping Protein; C495843:Capza1 protein, mouse; D011943:Receptors, Adrenergic, beta; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D000251:Adenosine Triphosphatases; D007545:Isoproterenol