title: Enhanced calcium cycling and contractile function in transgenic hearts expressing constitutively active G alpha o* protein.
abstract: In contrast to the other heterotrimeric GTP-binding proteins (G proteins) Gs and Gi, the functional role of G o is still poorly defined. To investigate the role of G alpha o in the heart, we generated transgenic mice with cardiac-specific expression of a constitutively active form of G alpha o1* (G alpha o*), the predominant G alpha o isoform in the heart. G alpha o expression was increased 3- to 15-fold in mice from 5 independent lines, all of which had a normal life span and no gross cardiac morphological abnormalities. We demonstrate enhanced contractile function in G alpha o* transgenic mice in vivo, along with increased L-type Ca2+ channel current density, calcium transients, and cell shortening in ventricular G alpha o*-expressing myocytes compared with wild-type controls. These changes were evident at baseline and maintained after isoproterenol stimulation. Expression levels of all major Ca2+ handling proteins were largely unchanged, except for a modest reduction in Na+/Ca2+ exchanger in transgenic ventricles. In contrast, phosphorylation of the ryanodine receptor and phospholamban at known PKA sites was increased 1.6- and 1.9-fold, respectively, in G alpha o* ventricles. Density and affinity of beta-adrenoceptors, cAMP levels, and PKA activity were comparable in G alpha o* and wild-type myocytes, but protein phosphatase 1 activity was reduced upon G alpha o* expression, particularly in the vicinity of the ryanodine receptor. We conclude that G alpha o* exerts a positive effect on Ca2+ cycling and contractile function. Alterations in protein phosphatase 1 activity rather than PKA-mediated phosphorylation might be involved in hyperphosphorylation of key Ca2+ handling proteins in hearts with constitutive G alpha o activation.
authors.affiliation: Division of Cardiology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhu
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Gach
authors.forename: GongXin
authors.initials: G
authors.lastname: Liu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Xu
authors.forename: Chee Chew
authors.initials: CC
authors.lastname: Lim
authors.forename: Julie X
authors.initials: JX
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.forename: Kurt
authors.initials: K
authors.lastname: Chuprun
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mende
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000257:Adenoviridae Infections / Q000473:pathology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology; D002469:Cell Separation; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D045304:Cytochromes c / Q000096:biosynthesis; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000096:biosynthesis*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009200:Myocardial Contraction / Q000235:genetics* / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D045304:Cytochromes c; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D007545:Isoproterenol; D002118:Calcium