Emerging concepts of receptor endocytosis and concurrent intracellular signaling: Mechanisms of guanylyl cyclase/natriuretic peptide receptor-A activation and trafficking.

Endocytosis is a prominent clathrin-mediated mechanism for concentrated uptake and internalization of ligand-receptor complexes, also known as cargo. Internalization of cargo is the fundamental mechanism for receptor-dependent regulation of cell membrane function, intracellular signal transduction, and neurotransmission, as well as other biological and physiological activities. However, the intrinsic mechanisms of receptor endocytosis and contemporaneous intracellular signaling are not well understood. We review emerging concepts of receptor endocytosis with concurrent intracellular signaling, using a typical example of guanylyl cyclase/natriuretic peptide receptor-A (NPRA) internalization, subcellular trafficking, and simultaneous generation of second-messenger cGMP and signaling in intact cells. We highlight the role of short-signal motifs located in the carboxyl-terminal regions of membrane receptors during their internalization and subsequent receptor trafficking in organelles that are not traditionally studied in this context, including nuclei and mitochondria. This review sheds light on the importance of future investigations of receptor endocytosis and trafficking in live cells and intact animals in vivo in physiological context.