Key result
Intracellular G protein-coupled receptors, including angiotensin II, endothelin, and β-adrenergic receptors on the cardiac nuclear envelope, play distinct roles in cardiovascular function and pathology.
Intracellular GPCRs on the nuclear membrane of cardiac cells are functional and regulate signaling pathways, suggesting that drug efficacy depends on both extracellular and intracellular receptor targeting.
May influence interpretation of GPCR-targeted therapies; leaves open whether nuclear receptors warrant specific drug design.
G protein-coupled receptors (GPCRs) play key physiological roles and represent a significant target for drug development. However, historically, drugs were developed with the understanding that GPCRs as a therapeutic target exist solely on cell surface membranes. More recently, GPCRs have been detected on intracellular membranes, including the nuclear membrane, and the concept that intracellular GPCRs are functional is become more widely accepted. Nuclear GPCRs couple to effectors and regulate signaling pathways, analogous to their counterparts at the cell surface, but may serve distinct biological roles. Hence, the physiological responses mediated by GPCR ligands, or pharmacological agents, result from the integration of their actions at extracellular and intracellular receptors. The net effect depends on the ability of a given ligand or drug to access intracellular receptors, as dictated by its structure, lipophilic properties, and affinity for nuclear receptors. This review will discuss angiotensin II, endothelin, and β-adrenergic receptors located on the nuclear envelope in cardiac cells in terms of their origin, activation, and role in cardiovascular function and pathology.
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Branco et al. (2015) conducted a review in Cardiovascular function and pathology. Nuclear G protein-coupled receptors (angiotensin II, endothelin, and β-adrenergic receptors) was evaluated. Intracellular G protein-coupled receptors, including angiotensin II, endothelin, and β-adrenergic receptors on the cardiac nuclear envelope, play distinct roles in cardiovascular function and pathology.
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