Receptor Fragments: Intracellular Signaling and Novel Therapeutic Targets

Abstract

Many conventional GPCRs such as those associated with apelin, endothelin, prostaglandin E2, and angiotensin have also been localized to the intracellular space, principally the nucleus. These observations have involved a broad range of tissues, isolated primary cells, and cell lines and a variety of techniques including confocal microscopy, immunohistochemistry, immunocytochemistry, and western blotting. Some receptors are transported to nucleus as holoreceptors while other receptors have been shown to be cleaved with only a portion of the receptor trafficking to nucleus. Several studies from many different laboratories indicate that, depending on the cell type, the angiotensin II type 1 receptor can exist in nuclear membrane or nucleosol and that nuclear accumulation can be induced by ligand-treatment. Moreover, a population of the angiotensin receptor is cleaved in response to angiotensin II and the cytoplasmic carboxyterminal fragment trafficks to nucleus and is a potent apoptotic reagent. In this review, we discuss AT1R cleavage in light of several other receptor cleavage events which similarly produce apoptotic fragments; functionally active intracellular cleavage fragments represent novel targets for drug development.