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.
*Montreal Heart Institute, Montréal, Québec, Canada;
Departments of †Biochemistry; and
‡Medicine, Université de Montréal, Montréal, Québec, Canada; and
§Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
Reprints: Bruce G. Allen, PhD, Department of Medicine, Montreal Heart Institute, Université de Montréal, 5000 Belanger St, Montréal, Québec H1T 1C8, Canada (e-mail: firstname.lastname@example.org).
Supported by the Canadian Institutes of Health Research (MOP-125970) and the Fondation des maladies du coeur du Québec.
The authors report no conflicts of interest.
Received September 08, 2014
Accepted November 11, 2014