Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy
Abstract
Increased adrenergic tone resulting from cardiovascular stress leads to development of heart failure, in part, through chronic stimulation of b1 adrenergic receptors (bARs) on cardiac myocytes. Blocking these receptors is part of the basis for b-blocker therapy for heart failure. Recent data demonstrate that G protein-coupled receptors (GPCRs), including bARs, are activated intracellularly, although the biological significance is unclear. Here we investigated the functional role of Golgi bARs in rat cardiac myocytes and found they activate Golgi localized, prohypertrophic, phosphoinositide hydrolysis, that is not accessed by cell surface bAR 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 b1ARs 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 b-blocker therapies.
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Funding
National Institutes of Health (R35GM127303)
- Alan V Smrcka
National Institutes of Health (R00HL122508)
- Roshanak Irannejad
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of Michigan protocol number PRO00009147.
Copyright
© 2019, Nash et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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