Ligand-mediated endocytosis and intracellular sequestration of guanylyl cyclase/natriuretic peptide receptors: role of GDAY motif

Abstract

The guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), also referred to as GC-A, is a single polypeptide molecule having a critical function in blood pressure regulation and cardiovascular homeostasis. GC-A/NPRA, which resides in the plasma membrane, consists of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular cytoplasmic region containing a protein kinase-like homology domain (KHD) and a guanylyl cyclase (GC) catalytic domain. After binding with atrial and brain natriuretic peptides (ANP and BNP), GC-A/NPRA is internalized and sequestered into intracellular compartments. Therefore, GC-A/NPRA is a dynamic cellular macromolecule that traverses different subcellular compartments through its lifetime. This review describes the roles of short-signal sequences in the internalization, trafficking, and intracellular redistribution of GC-A/NPRA from cell surface to cell interior. Evidence indicates that, after internalization, the ligand-receptor complexes dissociate inside the cell and a population of GC-A/NPRA recycles back to the plasma membrane. Subsequently, the disassociated ligands are degraded in the lysosomes. However a small percentage of the ligand escapes the lysosomal degradative pathway and is released intact into culture medium. By using pharmacologic and molecular perturbants, emphasis has been placed on the cellular regulation and processing of ligand-bound GC-A/NPRA in terms of receptor trafficking and down-regulation in intact cells. The discussion is concluded by examining the functions of short-signal sequence motifs in the cellular life-cycle of GC-A/NPRA, including endocytosis, trafficking, metabolic processing, inactivation, and/or down-regulation in model cell systems.

Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart

“…Therefore, the global cGMP increases observed in ANP treated cardiac fibroblasts may be attributed to low PDE5A expression in these cells (Fig. S1), or due to activation of intracellular ANP receptor guanylyl cyclase-A (GC-A) [46]. …”

Protein homeostasis and aging: The importance of exquisite quality control

“…Because the main emphasis of this review is on protein quality control, we will primarily focus on the removal of intracellular components through lysosomal degradation or autophagy, and will emphasize their role on protein turnover. Readers are encouraged to consult recent reviews on degradation of extracellular components and organelles by lysosomes (Farre et al, 2009; Fortini and Bilder, 2009; Kirkin et al, 2009; Kraft et al, 2009; Nichols, 2009; Pandey, 2009; Sorkin and von Zastrow, 2009; Tolkovsky, 2009). …”

Guanylyl cyclase / atrial natriuretic peptide receptor-A: role in the pathophysiology of cardiovascular regulation

“…At the protein level, ANG II inhibits the GC activity of NPRA (Arise & Pandey, 2006; Bottari et al, 1992; Haneda et al, 1991). Similarly, at the receptor level, NPRA is down-regulated by ANP or 8-bromo-cGMP (Liang et al, 2001; Pandey, 2010; Pandey et al, 2000; Pandey et al, 2005; Pandey et al, 2002). However, a complete understanding of the mechanisms of internalization and down-regulation of NPRA in physiological and pathological states remains to be established.…”