Guanylyl cyclase/natriuretic peptide receptor-A signaling antagonizes phosphoinositide hydrolysis, Ca(2+) release, and activation of protein kinase C.

Kailash N Pandey

doi:10.3389/fnmol.2014.00075

Abstract

Thus far, three related natriuretic peptides (NPs) and three distinct sub-types of cognate NP receptors have been identified and characterized based on the specific ligand binding affinities, guanylyl cyclase activity, and generation of intracellular cGMP. Atrial and brain natriuretic peptides (ANP and BNP) specifically bind and activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), and C-type natriuretic peptide (CNP) shows specificity to activate guanylyl cyclase/natriuretic peptide receptor-B (GC-B/NPRB). All three NPs bind to natriuretic peptide receptor-C (NPRC), which is also known as clearance or silent receptor. The NPRA is considered the principal biologically active receptor of NP family; however, the molecular signaling mechanisms of NP receptors are not well understood. The activation of NPRA and NPRB produces the intracellular second messenger cGMP, which serves as the major signaling molecule of all three NPs. The activation of NPRB in response to CNP also produces the intracellular cGMP; however, at lower magnitude than that of NPRA, which is activated by ANP and BNP. In addition to enhanced accumulation of intracellular cGMP in response to all three NPs, the levels of cAMP, Ca2+ and inositol triphosphate (IP3) have also been reported to be altered in different cells and tissue types. Interestingly, ANP has been found to lower the concentrations of cAMP, Ca2+, and IP3; however, NPRC has been proposed to increase the levels of these metabolic signaling molecules. The mechanistic studies of decreased and/or increased levels of cAMP, Ca2+, and IP3 in response to NPs and their receptors have not yet been clearly established. This review focuses on the signaling mechanisms of ANP/NPRA and their biological effects involving an increased level of intracellular accumulation of cGMP and a decreased level of cAMP, Ca2+, and IP3 in different cells and tissue systems.

Highlights

The principal role of C-type natriuretic peptide (CNP) is considered as a direct vasodilator involved in the regulation of vascular tone through activation of GC-B/NPRB on smooth muscle cells in the vascular beds (Hama et al, 1994). The objective of this current review is to summarize and document the findings and discoveries with particular emphasis of cellular signaling and physiological and pathological significance of ANP/NPRA in relation to the increased production of intracellular second messenger cGMP and inhibition of the phosphoinositide (IP3) hydrolysis, Ca2+ release, and protein kinase C (PKC) activity in target cells
Molecular cloning and expression of cDNA from mouse, rate, and human, led to identify and characterize the primary structure of three distinct subtypes of natriuretic peptides (NPs) receptors, which are currently designated as GC-A/NPRA, GC-B/NPRB, and natriuretic peptide receptor-C (NPRC)
Future investigations should include; the identification and characterization of cellular targets of intracellular second messenger cGMP produced by NPs, including cytosolic and nuclear proteins, role in gene transcription, cell growth and proliferation, apoptosis, and differentiation

Summary

INTRODUCTION

Atrial natriuretic factor/peptide (ANF/ANP) is produced and secreted in the specific granules of cardiac atrial myocytes, which participates in the control of extracellular fluid volume, electrolyte balance, and mean arterial pressure, it plays a central role in the maintenance and regulation of cardiovascular homeostasis (de Bold et al, 1981; de Bold, 1985; Brenner et al, 1990; AnandSrivastava and Trachte, 1993; Pandey, 2005, 2011). The principal role of CNP is considered as a direct vasodilator involved in the regulation of vascular tone through activation of GC-B/NPRB on smooth muscle cells in the vascular beds (Hama et al, 1994) The objective of this current review is to summarize and document the findings and discoveries with particular emphasis of cellular signaling and physiological and pathological significance of ANP/NPRA in relation to the increased production of intracellular second messenger cGMP and inhibition of the phosphoinositide (IP3) hydrolysis, Ca2+ release, and protein kinase C (PKC) activity in target cells. Molecular cloning and expression of cDNA from mouse, rate, and human, led to identify and characterize the primary structure of three distinct subtypes of NP receptors, which are currently designated as GC-A/NPRA, GC-B/NPRB, and NPRC

Cell type

CONCLUSION