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

Elife. 2019 Aug 21;8:e48167. doi: 10.7554/eLife.48167.

Abstract

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 rat cardiac myocytes and found they activate Golgi localized, prohypertrophic, phosphoinositide hydrolysis, that is not accessed by cell surface βAR 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 β1ARs 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 β-blocker therapies.

Keywords: GPCR; Golgi; adrenergic antagonists; cell biology; hypertrophy; mouse; phospholipase C; rat.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cardiomegaly / physiopathology*
  • Golgi Apparatus / enzymology
  • Golgi Apparatus / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Hydrolysis
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / metabolism*
  • Phosphatidylinositol Phosphates / metabolism*
  • Phosphoinositide Phospholipase C / metabolism*
  • Rats
  • Receptors, Adrenergic, beta-1 / metabolism*

Substances

  • Guanine Nucleotide Exchange Factors
  • Phosphatidylinositol Phosphates
  • Rapgef3 protein, rat
  • Receptors, Adrenergic, beta-1
  • phosphatidylinositol 4-phosphate
  • Phosphoinositide Phospholipase C
  • phospholipase C epsilon