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Regulation of cardiac nitric oxide signaling by nuclear ?-adrenergic and endothelin receptors.


ABSTRACT: At the cell surface, ?ARs and endothelin receptors can regulate nitric oxide (NO) production. ?-adrenergic receptors (?ARs) and type B endothelin receptors (ETB) are present in cardiac nuclear membranes and regulate transcription. The present study investigated the role of the NO pathway in the regulation of gene transcription by these nuclear G protein-coupled receptors. Nitric oxide production and transcription initiation were measured in nuclei isolated from the adult rat heart. The cell-permeable fluorescent dye 4,5-diaminofluorescein diacetate (DAF2 DA) was used to provide a direct assessment of nitric oxide release. Both isoproterenol and endothelin increased NO production in isolated nuclei. Furthermore, a ?3AR-selective agonist, BRL 37344, increased NO synthesis whereas the ?1AR-selective agonist xamoterol did not. Isoproterenol increased, whereas ET-1 reduced, de novo transcription. The NO synthase inhibitor l-NAME prevented isoproterenol from increasing either NO production or de novo transcription. l-NAME also blocked ET-1-induced NO-production but did not alter the suppression of transcription initiation by ET-1. Inhibition of the cGMP-dependent protein kinase (PKG) using KT5823 also blocked the ability of isoproterenol to increase transcription initiation. Furthermore, immunoblotting revealed eNOS, but not nNOS, in isolated nuclei. Finally, caged, cell-permeable isoproterenol and endothelin-1 analogs were used to selectively activate intracellular ?-adrenergic and endothelin receptors in intact adult cardiomyocytes. Intracellular release of caged ET-1 or isoproterenol analogs increased NO production in intact adult cardiomyocytes. Hence, activation of the NO synthase/guanylyl cyclase/PKG pathway is necessary for nuclear ?3ARs to increase de novo transcription. Furthermore, we have demonstrated the potential utility of caged receptor ligands in selectively modulating signaling via endogenous intracellular G protein-coupled receptors.

SUBMITTER: Vaniotis G 

PROVIDER: S-EPMC3735468 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Regulation of cardiac nitric oxide signaling by nuclear β-adrenergic and endothelin receptors.

Vaniotis George G   Glazkova Irina I   Merlen Clémence C   Smith Carter C   Villeneuve Louis R LR   Chatenet David D   Therien Michel M   Fournier Alain A   Tadevosyan Artavazd A   Trieu Phan P   Nattel Stanley S   Hébert Terence E TE   Allen Bruce G BG  

Journal of molecular and cellular cardiology 20130517


At the cell surface, βARs and endothelin receptors can regulate nitric oxide (NO) production. β-adrenergic receptors (βARs) and type B endothelin receptors (ETB) are present in cardiac nuclear membranes and regulate transcription. The present study investigated the role of the NO pathway in the regulation of gene transcription by these nuclear G protein-coupled receptors. Nitric oxide production and transcription initiation were measured in nuclei isolated from the adult rat heart. The cell-perm  ...[more]

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