Elsevier

Cellular Signalling

Volume 13, Issue 4, April 2001, Pages 221-231
Cellular Signalling

Review Article
Natriuretic peptide signalling: molecular and cellular pathways to growth regulation

https://doi.org/10.1016/S0898-6568(01)00139-5Get rights and content

Abstract

The natriuretic peptides (NPs) constitute a family of polypeptide hormones that regulate mammalian blood volume and blood pressure. The ability of the NPs to modulate cardiac hypertrophy and cell proliferation as well is now beginning to be recognized. The NPs interact with three membrane-bound receptors, all of which contain a well-characterized extracellular ligand-binding domain. The R1 subclass of NP receptors (NPR-A and NPR-B) contains a C-terminal guanylyl cyclase domain and is responsible for most of the NPs downstream actions through their ability to generate cGMP. The R2 subclass lacks an obvious catalytic domain and functions primarily as a clearance receptor. This review focuses on the signal transduction pathways initiated by ligand binding and other factors that help to determine signalling specificities, including allosteric factors modulating cGMP generation, receptor desensitization, the activation and function of cGMP-dependent protein kinase (PKG), and identification of potential nuclear or cytoplasmic targets such as the mitogen-activated protein kinase signalling (MAPK) cascade. The inhibition of cardiac growth and hypertrophy may be an important but underappreciated action of the NP signalling system.

Introduction

Natriuretic peptides (NPs) are a family of polypeptide hormones that regulate blood pressure and blood volume by direct effects on the kidney and the systemic vasculature [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. More recently, the ability of NPs to modulate cell growth, both cell proliferation [11], [12], [13], [14], [15] and cardiomyocyte hypertrophy [16], [17], [18], has received attention. The biological activities of the NPs are initiated by their binding to cell-surface receptors of two types: R1 receptors that contain a cytoplasmic C-terminal guanylyl cyclase catalytic domain (NPR-A, NPR-B) and R2 receptors that have no intrinsic cyclase activity (NPR-C). Downstream signalling events involve the generation of cGMP, since many of the ligand-induced effects can be mimicked by the administration of cGMP analogues. However, the NPR-C clearance receptor may have unique effects that are cGMP-independent [19]. The precise signalling events leading to diverse physiologic responses remain to be elucidated. A given biological effect is the result of a critical interplay between ligand specificities, the distribution of different receptor types throughout the body, and the specific cell and tissue type-dependent signalling systems activated. This review will attempt to place the effects of the NPs on growth within this context.

Section snippets

Historical background

Henry et al. in 1955 [20] first suggested that the heart might be capable of sensing the “fullness” of the vascular bed and thus regulate it by modulating urine flow. The observation that administration of atrial but not ventricular extracts was capable of eliciting profound natriuresis, diuresis, and hypotension in rats provided the first evidence that the cardiac atria secreted a blood volume-regulating hormone. Jamieson and Palade [21] had already postulated that cytoplasmic granules in

Ligands

ANP and the B- and C-type NPs form a family of distinct but structurally similar molecules (Fig. 1). A fourth NP, DNP, has recently been found to have potent natriuretic activity in humans [34]. Every NP family member described thus far contains a disulfide bond between two cysteine residues, producing a ring structure that appears to be essential for receptor recognition and biological function [35]. All NP's are initially synthesized as precursors that are posttranslationally modified. In the

Receptors

As shown in Table 1, the NP receptors are widely distributed throughout the tissues of the body, including kidney, vascular smooth muscle, adrenal gland, intestine, heart, brain, bone, lung, gonad, and others [62], [63], [64], [65], [66], [67]. Consequently, it is difficult to assign biological function on the basis of differences in receptor distribution.

The NPR-A and NPR-B receptors possess intrinsic guanylyl cyclase activity, and are remarkably similar in their overall topology (Fig. 2).

Protein kinase G and other downstream targets

The cyclic nucleotide cAMP mediates the action of numerous hormones and neurotransmitters through its ability to activate cAMP-dependent protein kinase (PKA) [99]. The role of cGMP as a second messenger has long been appreciated, but the mechanism of action has only been addressed in the last decade [100], [101]. Most of cGMP's downstream actions [102], and possibly some of cAMP's actions [103], involve activation of PKGs. Unlike cAMP, however, cGMP has been found to regulate other protein

Regulation of cellular proliferation and cardiac hypertrophy

ANP has antiproliferative effects in a variety of tissues, including renal mesangial cells [11], [15], [133], astrocytes [134], [135], endothelial cells [136], cardiac fibroblasts [137], and vascular smooth muscle cells [11], [12], [14], [136], [138]. Extracellular matrix production is suppressed in smooth muscle [139] by PKG and ANP inhibits collagen synthesis by cardiac fibroblasts [140]. ANP also inhibits hypertrophy in primary cultures of cardiac myocytes [16], [17], [18]. Since the ANP

Conclusion

In the brief 20 years since the discovery of the NP system, there has been an explosion of research both in the basic and clinical fields. Much remains to be learned regarding the mechanisms of ANP action, including the diverse stimuli leading to its synthesis and secretion, the specificity of the known ligands, the role of receptor desensitization in modulating downstream signalling events, and the ultimate cytosolic and nuclear targets of the ANP signal. The clinical relevance of the NP

Acknowledgements

The authors would like to thank Richard H. Goodman, MD, PhD, for critical reading of the manuscript.

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