Nuclear membrane receptors for ET-1 in cardiovascular function

Abstract

Plasma membrane endothelin type A (ETA) receptors are internalized and recycled to the plasma membrane, whereas endothelin type B (ETB) receptors undergo degradation and subsequent nuclear translocation. Recent studies show that G protein-coupled receptors (GPCRs) and ion transporters are also present and functional at the nuclear membranes of many cell types. Similarly to other GPCRs, ETA and ETB are present at both the plasma and nuclear membranes of several cardiovascular cell types, including human cardiac, vascular smooth muscle, endocardial endothelial, and vascular endothelial cells. The distribution and density of ETARs in the cytosol (including the cell membrane) and the nucleus (including the nuclear membranes) differ between these cell types. However, the localization and density of ET-1 and ETB receptors are similar in these cell types. The extracellular ET-1-induced increase in cytosolic ([Ca]c) and nuclear ([Ca]n) free Ca2+ is associated with an increase of cytosolic and nuclear reactive oxygen species. The extracellular ET-1-induced increase of [Ca]c and [Ca]n as well as intracellular ET-1-induced increase of [Ca]n are cell-type dependent. The type of ET-1 receptor mediating the extracellular ET-1-induced increase of [Ca]c and [Ca]n depends on the cell type. However, the cytosolic ET-1-induced increase of [Ca]n does not depend on cell type. In conclusion, nuclear membranes' ET-1 receptors may play an important role in overall ET-1 action. These nuclear membrane ET-1 receptors could be targets for a new generation of antagonists.