β-Adrenergic Receptors: Not Always Outside-In

Canonical activation of G protein-coupled receptors (GPCRs) by hormone binding occurs at the plasma membrane, resulting in the diffusion of second messengers to intracellular effector sites throughout the cell. In contrast, recent evidence suggests that functional GPCRs can induce signaling from distinct intracellular domains, contributing to specificity in signaling. Functional adrenergic receptors have been identified at intracellular sites in the cardiac myocyte such as endosomes, the sarcoplasmic reticulum, the Golgi, and the inner nuclear membrane. These receptors are key regulators of cardiac physiology, mediating the response of the heart to sympathetic stimulation. Under conditions of prolonged cardiac stress leading to chronic adrenergic receptor stimulation, these receptors stimulate pathways that lead to cardiac pathophysiology such as myocyte hypertrophy, apoptosis, and fibrosis, ultimately leading to heart failure. Hence, significant work has resulted in the pharmacological modulation of β-adrenergic receptors for therapeutic benefit. Here, we discuss how the localization of β₁- and β₂-adrenergic receptors to different sites within the cardiac myocyte dictates control over specific physiological and pathological events. We discuss how therapeutically targeting receptors at these distinct sites may be used for the treatment of cardiac disease.