FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4377029593> ?p ?o ?g. }

• W4377029593 abstract "<b>Abstract ID 24004</b> <b>Poster Board 109</b> Chronic overstimulation of Gs-coupled ß-adrenergic receptor (ß-AR) signaling by catecholamines, induces pathological cardiac hypertrophy and ultimately heart failure. ß1-ARs and ß2-ARs are the two major subtypes of ß-ARs present in the human heart and mediate the activity of sympathetic nervous system. It is known that ß1-ARs and ß2-ARs elicit significantly different or even opposite effects on cardiac functions such as contractility and heart failure, though they share overall sequence and structural homology, and both stimulate cAMP production. The molecular mechanisms underlying these distinct biological effects have not been fully elucidated. Previously, our laboratory demonstrated that a cAMP/EPAC/phospholipase Ce (PLCe)-mediated signaling pathway at the Golgi apparatus is important for regulation of cardiac hypertrophy. We also showed that this pathway is selectively stimulated by activation of ß1-ARs localized at Golgi apparatus but not those at the plasma membrane (PM). Access to intracellular ß1-ARs by catecholamines was mediated by the organic cation transporters (OCTs), and blockade of OCT3 inhibited catecholamine stimulated cardiomyocyte hypertrophy. In my current study using adult ventricular cardiac myocytes, I found that the activation of PM ß2-ARs opposes stimulation of the prohypertrophic EPAC/PLCe pathway at the Golgi apparatus by either Angiotensin II, or Golgi localized ß1-ARs. ß2-AR-dependent inhibition appears to be at the level of PLCe since activation of ß2-AR with salmeterol blocks direct activation of EPAC/PLCe by the EPAC selective cAMP analog 8-(4-chlorophenylthio)-2′-<i>O</i>-methyl-cAMP (CPTOMe)-AM, and blocks PLCeactivation by ATII which activates PLCe through a pathway that does not rely on EPAC. Blockade of internalization of ß2-ARs with Dyngo-4A abolished this inhibitory signaling. Downstream of ß2-ARs, I found that ß2-AR-dependent PLCe inhibition is not mediated by PKA. Rather, blockade of Gi with PTX, or Gbg with gallein, inhibited the ability of ß2-ARs to block Golgi PLCe activity. Additionally, inhibition of ERK activation by PD0325901 abolished ß2-AR-mediated inhibition of Golgi PLCe activity. This supports a model where ß2ARs internalized from the plasma membrane activate Gi releasing Gbg subunits leading to ERK activation and inhibition of PI hydrolysis at the Golgi apparatus, thereby inhibiting hypertrophic signaling by PLCe. This study reveals a novel potential mechanism for ß2-AR antagonism of the Epac/PLCe pathway that may contribute to the known protective effects of ß2AR signaling on the development of heart failure. Elucidation of a mechanism for the anti-hypertrophic versus hypertrophic signaling balance from ß1-ARs and ß2-ARs gives critical insights into the development of new strategies for treatment of heart failure by targeting ßAR subtypes." @default.
• W4377029593 created "2023-05-19" @default.
• W4377029593 creator A5002671842 @default.
• W4377029593 creator A5022873764 @default.
• W4377029593 date "2023-05-18" @default.
• W4377029593 modified "2023-10-16" @default.
• W4377029593 title "Opposing effects of ß2-ARs on ß1-ARs on phospholipase C-mediated cardiac hypertrophic signaling" @default.
• W4377029593 doi "https://doi.org/10.1124/jpet.122.240040" @default.
• W4377029593 hasPublicationYear "2023" @default.
• W4377029593 type Work @default.
• W4377029593 citedByCount "0" @default.
• W4377029593 crossrefType "proceedings-article" @default.
• W4377029593 hasAuthorship W4377029593A5002671842 @default.
• W4377029593 hasAuthorship W4377029593A5022873764 @default.
• W4377029593 hasBestOaLocation W43770295931 @default.
• W4377029593 hasConcept C119062480 @default.
• W4377029593 hasConcept C126322002 @default.
• W4377029593 hasConcept C12927208 @default.
• W4377029593 hasConcept C134018914 @default.
• W4377029593 hasConcept C158617107 @default.
• W4377029593 hasConcept C170493617 @default.
• W4377029593 hasConcept C181199279 @default.
• W4377029593 hasConcept C185592680 @default.
• W4377029593 hasConcept C24998067 @default.
• W4377029593 hasConcept C2778597717 @default.
• W4377029593 hasConcept C2908929049 @default.
• W4377029593 hasConcept C39133596 @default.
• W4377029593 hasConcept C55493867 @default.
• W4377029593 hasConcept C62478195 @default.
• W4377029593 hasConcept C71924100 @default.
• W4377029593 hasConcept C79879829 @default.
• W4377029593 hasConcept C86803240 @default.
• W4377029593 hasConcept C95444343 @default.
• W4377029593 hasConceptScore W4377029593C119062480 @default.
• W4377029593 hasConceptScore W4377029593C126322002 @default.
• W4377029593 hasConceptScore W4377029593C12927208 @default.
• W4377029593 hasConceptScore W4377029593C134018914 @default.
• W4377029593 hasConceptScore W4377029593C158617107 @default.
• W4377029593 hasConceptScore W4377029593C170493617 @default.
• W4377029593 hasConceptScore W4377029593C181199279 @default.
• W4377029593 hasConceptScore W4377029593C185592680 @default.
• W4377029593 hasConceptScore W4377029593C24998067 @default.
• W4377029593 hasConceptScore W4377029593C2778597717 @default.
• W4377029593 hasConceptScore W4377029593C2908929049 @default.
• W4377029593 hasConceptScore W4377029593C39133596 @default.
• W4377029593 hasConceptScore W4377029593C55493867 @default.
• W4377029593 hasConceptScore W4377029593C62478195 @default.
• W4377029593 hasConceptScore W4377029593C71924100 @default.
• W4377029593 hasConceptScore W4377029593C79879829 @default.
• W4377029593 hasConceptScore W4377029593C86803240 @default.
• W4377029593 hasConceptScore W4377029593C95444343 @default.
• W4377029593 hasLocation W43770295931 @default.
• W4377029593 hasOpenAccess W4377029593 @default.
• W4377029593 hasPrimaryLocation W43770295931 @default.
• W4377029593 hasRelatedWork W1971613811 @default.
• W4377029593 hasRelatedWork W1979064111 @default.
• W4377029593 hasRelatedWork W2001085103 @default.
• W4377029593 hasRelatedWork W2003079269 @default.
• W4377029593 hasRelatedWork W2054593959 @default.
• W4377029593 hasRelatedWork W2054992011 @default.
• W4377029593 hasRelatedWork W2064416809 @default.
• W4377029593 hasRelatedWork W2077755216 @default.
• W4377029593 hasRelatedWork W2162471541 @default.
• W4377029593 hasRelatedWork W2417520021 @default.
• W4377029593 isParatext "false" @default.
• W4377029593 isRetracted "false" @default.
• W4377029593 workType "article" @default.