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Golgi localized ?1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLC? to regulate cardiac hypertrophy.


ABSTRACT: Increased adrenergic tone resulting from cardiovascular stress leads to development of heart failure, in part, through chronic stimulation of ?1 adrenergic receptors (?ARs) on cardiac myocytes. Blocking these receptors is part of the basis for ?-blocker therapy for heart failure. Recent data demonstrate that G protein-coupled receptors (GPCRs), including ?ARs, are activated intracellularly, although the biological significance is unclear. Here we investigated the functional role of Golgi ?ARs in rat cardiac myocytes and found they activate Golgi localized, prohypertrophic, phosphoinositide hydrolysis, that is not accessed by cell surface ?AR stimulation. This pathway is accessed by the physiological neurotransmitter norepinephrine (NE) via an Oct3 organic cation transporter. Blockade of Oct3 or specific blockade of Golgi resident ?1ARs prevents NE dependent cardiac myocyte hypertrophy. This clearly defines a pathway activated by internal GPCRs in a biologically relevant cell type and has implications for development of more efficacious ?-blocker therapies.

SUBMITTER: Nash CA 

PROVIDER: S-EPMC6726460 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy.

Nash Craig A CA   Wei Wenhui W   Irannejad Roshanak R   Smrcka Alan V AV  

eLife 20190821


Increased adrenergic tone resulting from cardiovascular stress leads to development of heart failure, in part, through chronic stimulation of β1 adrenergic receptors (βARs) on cardiac myocytes. Blocking these receptors is part of the basis for β-blocker therapy for heart failure. Recent data demonstrate that G protein-coupled receptors (GPCRs), including βARs, are activated intracellularly, although the biological significance is unclear. Here we investigated the functional role of Golgi βARs in  ...[more]

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