Internalized beta2-Adrenergic Receptors Inhibit Subcellular Phospholipase C-Dependent Cardiac Hypertrophic Signaling

Abstract

Chronically elevated neurohumoral drive, and particularly elevated adrenergic tone leading to {beta}-adrenergic receptor ({beta}-AR) overstimulation in cardiac myocytes, is a key mechanism involved in the progression of heart failure. {beta}1-AR and {beta}2-ARs are the two major subtypes of {beta}-ARs present in the human heart, however, they elicit different or even opposite effects on cardiac function and hypertrophy. For example, chronic activation of {beta}1ARs drives detrimental cardiac remodeling while {beta}2AR signaling is protective. The underlying molecular mechanisms for cardiac protection through {beta}2ARs remain unclear. Here we show that {beta}2-AR protects against hypertrophy through inhibition of PLC{varepsilon} signaling at the Golgi apparatus. The mechanism for {beta}2AR-mediated PLC inhibition requires internalization of {beta}2AR, activation of Gi and G{beta}{gamma} subunit signaling at endosomes and ERK activation. This pathway inhibits both angiotensin II and Golgi-{beta}1-AR-mediated stimulation of phosphoinositide hydrolysis at the Golgi apparatus ultimately resulting in decreased PKD and HDAC5 phosphorylation and protection against cardiac hypertrophy. This reveals a mechanism for {beta}2-AR antagonism of the PLC{varepsilon} pathway that may contribute to the known protective effects of {beta}2-AR signaling on the development of heart failure.