Nuclear membrane receptors for ET-1 in cardiovascular function

Abstract

Plasma membrane endothelin type A (ET(A)) receptors are internalized and recycled to the plasma membrane, whereas endothelin type B (ET(B)) 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, ET(A) and ET(B) 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 ET(A)Rs 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 ET(B) receptors are similar in these cell types. The extracellular ET-1-induced increase in cytosolic ([Ca](c)) and nuclear ([Ca](n)) free Ca(2+) 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.

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

“…Intracrine signalling refers to a process whereby a ligand, originating within a target cell or taken up from the extracellular milieu, acts upon an intracellular receptor (reviewed in [9][10][11][62][63][64][65][66][67]). The origin of the ligand for endogenous endothelin receptors remains unknown.…”

“…However, endothelin receptors, as well as several other GPCRs and their effectors, are also present on cardiac nuclear membranes (reviewed in [9][10][11]). Immunocytofluorescence studies have revealed ETA to be primarily in the plasma membrane with some perinuclear staining, whereas ETB localize to the nuclear membrane in ventricular myocytes [12,13].…”

Intracellular Endothelin Type B Receptor-driven Ca2+ Signal Elicits Nitric Oxide Production in Endothelial Cells

“…ET-1 acts also as an intracrine, activating intracellular cognate receptors (2). Stimulation of ET-1 receptors at the plasma or nuclear membrane induces Ca 2ϩ release, NO, and reactive oxygen species formation in the cytosol or nucleus (5,30). Cardiovascular disease pathogenesis involves oxidative stress and further alteration of ET-1 and NO signaling pathways (30, 31).…”

“…In the cardiovascular human and rodent cells, ET A and ET B are localized to the plasma membrane, cytoplasm, nuclear membranes, and nucleoplasm (4 -6). ET-1 elevates both cytosolic and nuclear Ca 2ϩ concentrations; the rise in cysotolic Ca 2ϩ concentration, [Ca 2ϩ ] i , in response to ET-1 is seen in both intact and membrane-perforated cells (5). Moreover, ET-1 is involved in nitric oxide (NO) and reactive oxygen species generation both in the cytosol and in the nucleus (5).…”

“…Although the stimulation of nuclear membrane receptors elicits events largely restricted to the nucleus (3,5), receptors located on the membrane of other organelles trigger signaling cascades within the cytoplasm, resulting in rapid cell responses. Because ET B receptors were identified in the endolysosomal system (7)(8)(9), in this study, we examined whether or not endolysosomal ET B receptors are involved in Ca 2ϩ signaling and NO production in rat pulmonary microvascular endothelial cells (RPMVEC), which express ET B receptors (10 -12).…”