G protein-coupled receptor signalling in the cardiac nuclear membrane: evidence and possible roles in physiological and pathophysiological function

Abstract

G protein-coupled receptors (GPCRs) play key physiological roles in numerous tissues, including the heart, and their dysfunction influences a wide range of cardiovascular diseases. Recently, the notion of nuclear localization and action of GPCRs has become more widely accepted. Nuclear-localized receptors may regulate distinct signalling pathways, suggesting that the biological responses mediated by GPCRs are not solely initiated at the cell surface but may result from the integration of extracellular and intracellular signalling pathways. Many of the observed nuclear effects are not prevented by classical inhibitors that exclusively target cell surface receptors, presumably because of their structures, lipophilic properties, or affinity for nuclear receptors. In this topical review, we discuss specifically how angiotensin-II, endothelin, β-adrenergic and opioid receptors located on the nuclear envelope activate signalling pathways, which convert intracrine stimuli into acute responses such as generation of second messengers and direct genomic effects, and thereby participate in the development of cardiovascular disorders.

Figure 1. Known nuclear angiotensin II, β-adrenergic, endothelin and opioid receptor-activated signalling cascades in the heart

Different receptor systems activate distinct Gα-GTP and Gβγ complexes which stimulate downstream effector molecules modulating the production or release of second messengers (e.g. Ca²⁺, cAMP, NO, IP₃) which may ultimately lead to changes in gene transcription. Considering the potential physiological functions of nuclear GPCRs in various cardiovascular diseases, future studies may provide a foundation for selective pharmacological interventions targeting these systems.

Figure 2. Sources of intracrine ligands

Intracrine systems appear in various forms; hormones, cardiac growth factors, DNA-binding proteins and enzymes can all display intracrine functionality. There are many ways to generate intracrine ligands: (1) ligands can be synthesized within the cell and remain in the cytoplasm where they can be trafficked to organelles such as the nucleus (e.g. ET-1); (2) ligands may pass through channels or pores, or active transport across the plasma membrane (e.g. noradrenaline, NA); (3) ligands sufficiently small may cross the plasma membrane directly, while hydrophobic ligands may freely cross the plasma membrane at will (e.g. leukotrienes, LTs); (4) internalization of endogeneously or exogenously formed ligands following binding to cell-surface receptors and subsequent release from internalized endosomes within the cell (e.g. opioids).