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.
Highlights
Cardiovascular disease, heart failure, is the leading cause of disease and death in the developed world
We demonstrate that endogenous b1ARs at the Golgi apparatus in cardiac myocytes are required to stimulate hypertrophic Epac/PLCe-dependent PI4P hydrolysis at the Golgi, and that these intracellular badrenergic receptors (bARs) can be accessed by physiological neurotransmitters, and synthetic b-blockers and agonists
In previous studies we showed that cAMP produced upon stimulation with the bAR agonist, Iso, does not induce PI4P hydrolysis at the Golgi in NRVMs without addition of a PDE3 inhibitor [17]
Summary
Cardiovascular disease, heart failure, is the leading cause of disease and death in the developed world. In response to long term pathological stress, such as hypertension or myocardial infarction, the levels of neurohumoral factors such as epinephrine, endothelin and angiotensin II increase. These hormones directly stimulate G protein-coupled receptors (GPCRs), including b-adrenergic receptors in cardiac myocytes [1,2,3]. Chronic stimulation of these receptors, including stimulation of badrenergic receptors (bARs) by catecholamines, drives cardiac hypertrophy and ventricular remodeling, leading to heart failure. PLCe is poised as a nexus for multiple receptor signaling systems due its diversity of upstream regulators including heterotrimeric G protein bg subunits and small GTPases, including Rap, Rho and Ras, and cAMP via the Rap guanine nucleotide exchange factor (GEF), Epac (1014)
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