Abstract
The targeted endocytosis and redistribution of transmembrane receptors among membrane-bound subcellular organelles are vital for their correct signaling and physiological functions. Membrane receptors committed for internalization and trafficking pathways are sorted into coated vesicles. Cardiac hormones, atrial and brain natriuretic peptides (ANP and BNP) bind to guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) and elicit the generation of intracellular second messenger cyclic guanosine 3',5'-monophosphate (cGMP), which lowers blood pressure and incidence of heart failure. After ligand binding, the receptor is rapidly internalized, sequestrated, and redistributed into intracellular locations. Thus, NPRA is considered a dynamic cellular macromolecule that traverses different subcellular locations through its lifetime. The utilization of pharmacologic and molecular perturbants has helped in delineating the pathways of endocytosis, trafficking, down-regulation, and degradation of membrane receptors in intact cells. This review describes the investigation of the mechanisms of internalization, trafficking, and redistribution of NPRA compared with other cell surface receptors from the plasma membrane into the cell interior. The roles of different short-signal peptide sequence motifs in the internalization and trafficking of other membrane receptors have been briefly reviewed and their potential significance in the internalization and trafficking of NPRA is discussed.
Highlights
Atrial natriuretic peptide (ANP) belongs to the natriuretic peptide (NP) hormone family and exerts natriuretic, diuretic, vasorelaxant, antiproliferative, and anti-inflammatory responses, largely directed to the reduction of blood pressure and blood volume [1,2,3]
This review describes the investigation of the mechanisms of internalization, trafficking, and redistribution of NPRA compared with other cell surface receptors from the plasma membrane into the cell interior
Studies using Leydig tumor (MA-10) cells containing a high-density of endogenous NPRA and human embryonic kidney-293 (HEK-293) as well as COS-7 cells expressing recombinant NPRA, established that ligand-receptor complexes of ANP-NPRA are rapidly internalized in a ligand-dependent manner and redistributed intracellularly in intact cells [20,21,24,71,93]
Summary
Atrial natriuretic peptide (ANP) belongs to the natriuretic peptide (NP) hormone family and exerts natriuretic, diuretic, vasorelaxant, antiproliferative, and anti-inflammatory responses, largely directed to the reduction of blood pressure and blood volume [1,2,3]. Evidence suggests that after internalization, a large population of ANP/NPRA ligand-receptor complexes are degraded in lysosomes and a small population of receptor recycles back to the plasma membrane [24,25,26]. It is believed that internalization of receptors is usually carried out by clathrin-coated vesicles formed on the plasma membrane, and seems to function in a small-peptide sequence-dependent manner. The bound ligand-receptor complexes of NPRC are internalized, degraded in the lysosomal compartments, and recycle back to the membrane [35] JMD, juxtamembrane domain; KHD, kinase like homology domain; DD, dimerization domain; GCD, guanylyl cyclase catalytic domain. The intact ligand can rebind to recycled receptor on the plasma membrane and reenter the cell via a repeated process of internalization, termed as retroendocytosis [25]
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