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

  1. Craig A Nash
  2. Wenhui Wei
  3. Roshanak Irannejad
  4. Alan V Smrcka  Is a corresponding author
  1. University of Michigan, United States
  2. University of California, San Francisco, United States
Research Article
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Cite this article as: eLife 2019;8:e48167 doi: 10.7554/eLife.48167


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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Author details

  1. Craig A Nash

    Department of Pharmacology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wenhui Wei

    Department of Pharmacology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Roshanak Irannejad

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alan V Smrcka

    Department of Pharmacology, University of Michigan, Ann Arbor, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3099-8812


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.


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.

Reviewing Editor

  1. Adam Linstedt, Carnegie Mellon University, United States

Publication history

  1. Received: May 3, 2019
  2. Accepted: August 21, 2019
  3. Accepted Manuscript published: August 21, 2019 (version 1)
  4. Version of Record published: September 4, 2019 (version 2)


© 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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