Dataset Information

NF2 signaling pathway plays a pro-apoptotic role in ?-adrenergic receptor stimulated cardiac myocyte apoptosis.

ABSTRACT: Treatment of adult rat ventricular myocytes (ARVMs) with ?-AR agonist (isoproterenol) for 15 min increased phosphorylation (serine-518) and sumoylation of NF2. Co-immunoprecipitation assay confirmed ?-AR-stimulated sumoylation of NF2. ?-AR stimulation enhanced nuclear translocation of phosphorylated and sumoylated NF2. Specific inhibition of ?1-AR and protein kinase A (PKA) decreased ?-AR-stimulated increase in NF2 post-translational modifications, while inhibition of ?2-AR had no effect. Activation of adenylyl cyclase using forskolin (FSK) mimicked the effects of ?-AR stimulation. ?-AR stimulation and expression of wild-type (WT)-NF2 using adenoviruses increased phosphorylation of mammalian sterile like kinase-1/2 (MST1/2) and yes activated protein (YAP), downstream targets of NF2. Knockdown of NF2 using siRNA in H9C2 cardiomyocytes decreased ?-AR-stimulated increase in NF2 and YAP phosphorylation. siRNA-mediated knockdown of NF2 decreased ?-AR-stimulated increase in apoptosis, while expression of WT-NF2 induced apoptosis in ARVMs. Expression of WT-NF2 stimulated the mitochondrial death pathway as evidenced by activation of c-Jun N-terminal Kinases (JNKs), and increase in cytosolic cytochrome c levels and Bax expression.?-AR stimulation affects post-translational modifications of NF2 via the involvement ?1-AR/PKA/cAMP pathway, and NF2 plays a pro-apoptotic role in ?-AR-stimulated myocyte apoptosis via the phosphorylation (inactivation) of YAP and involvement of mitochondrial death pathway.

SUBMITTER: Dalal S

PROVIDER: S-EPMC5927447 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

NF2 signaling pathway plays a pro-apoptotic role in β-adrenergic receptor stimulated cardiac myocyte apoptosis.

Dalal Suman S Connelly Barbara B Singh Mahipal M Singh Krishna K

PloS one 20180430 4

<h4>Methods and results</h4>Treatment of adult rat ventricular myocytes (ARVMs) with β-AR agonist (isoproterenol) for 15 min increased phosphorylation (serine-518) and sumoylation of NF2. Co-immunoprecipitation assay confirmed β-AR-stimulated sumoylation of NF2. β-AR stimulation enhanced nuclear translocation of phosphorylated and sumoylated NF2. Specific inhibition of β1-AR and protein kinase A (PKA) decreased β-AR-stimulated increase in NF2 post-translational modifications, while inhibition of ...[more]

PMID: 29709009

Similar Datasets

Project description:A five-state model of myofilament contraction was integrated into a well-established rabbit ventricular myocyte model of ion channels, Ca(2+) transporters and kinase signaling to analyze the relative contribution of different phosphorylation targets to the overall mechanical response driven by ?-adrenergic stimulation (?-AS). ?-AS effect on sarcoplasmic reticulum Ca(2+) handling, Ca(2+), K(+) and Cl(-) currents, and Na(+)/K(+)-ATPase properties was included based on experimental data. The inotropic effect on the myofilaments was represented as reduced myofilament Ca(2+) sensitivity (XBCa) and titin stiffness, and increased cross-bridge (XB) cycling rate (XBcy). Assuming independent roles of XBCa and XBcy, the model reproduced experimental ?-AS responses on action potentials and Ca(2+) transient amplitude and kinetics. It also replicated the behavior of force-Ca(2+), release-restretch, length-step, stiffness-frequency and force-velocity relationships, and increased force and shortening in isometric and isotonic twitch contractions. The ?-AS effect was then switched off from individual targets to analyze their relative impact on contractility. Preventing ?-AS effects on L-type Ca(2+) channels or phospholamban limited Ca(2+) transients and contractile responses in parallel, while blocking phospholemman and K(+) channel (IKs) effects enhanced Ca(2+) and inotropy. Removal of ?-AS effects from XBCa enhanced contractile force while decreasing peak Ca(2+) (due to greater Ca(2+) buffering), but had less effect on shortening. Conversely, preventing ?-AS effects on XBcy preserved Ca(2+) transient effects, but blunted inotropy (both isometric force and especially shortening). Removal of titin effects had little impact on contraction. Finally, exclusion of ?-AS from XBCa and XBcy while preserving effects on other targets resulted in preserved peak isometric force response (with slower kinetics) but nearly abolished enhanced shortening. ?-AS effects on XBCa and XBcy have greater impact on isometric and isotonic contraction, respectively.

Dataset Information

NF2 signaling pathway plays a pro-apoptotic role in ?-adrenergic receptor stimulated cardiac myocyte apoptosis.

Publications

NF2 signaling pathway plays a pro-apoptotic role in β-adrenergic receptor stimulated cardiac myocyte apoptosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets