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 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.

Subcellular Organization of the cAMP Signaling Pathway

“…A number of studies have also documented cAMP signaling from intracellular GPCRs that are located at intracellular membranes independently from receptor internalization ( Kumar et al, 2008 ; Suofu et al, 2017 ; Dahl et al, 2018 ; Nash et al, 2019 ). For example, studies show that a pre-existing β 1 -AR receptor pool that is not delivered from the cell surface resides at the Golgi, where it can be activated by endogenous ligands that enter the cell by facilitated transport via the organic cation transporter 3 ( Irannejad et al, 2017 ).…”

“…For example, studies show that a pre-existing β 1 -AR receptor pool that is not delivered from the cell surface resides at the Golgi, where it can be activated by endogenous ligands that enter the cell by facilitated transport via the organic cation transporter 3 ( Irannejad et al, 2017 ). Activation of this internal pool of receptors induces Epac-phospholipase C ε (PLC ε )–dependent phosphatidylinositol-4-phosphate (PI4P) hydrolysis in a process that has been linked to catecholamine-dependent cardiomyocyte hypertrophy ( Nash et al, 2019 ).…”

Optogenetic control of small GTPases reveals RhoA-mediated intracellular calcium signaling

“…PLCε was recently reported to be activated at the Golgi, and not at the PM in cardiac cells, to hydrolyze phosphatidylinositol 4-phosphate [PI(4)P] (Malik et al, 2015; Nash et al, 2019; Zhang et al, 2013). Our optogenetic system, iLID-CAAX KRas , largely localizes to the PM but is also partially localized in the Golgi.…”

Location Bias as Emerging Paradigm in GPCR Biology and Drug Discovery

“…Activation of Golgi β 1 AR triggers Golgi internal G s -mediated cAMP response contributing to overall cellular β 1 AR-mediated cAMP level changes ( Figure 1 I) ( Irannejad et al., 2017 ). This effect seems to be physiologically relevant since it is recently shown that blocking of Golgi β 1 AR inhibits norepinephrine-induced cardiac myocyte hypertrophy ( Nash et al., 2019 ).…”