Atrial natriuretic peptide (ANP) is a vasoactive peptide hormone generated in the atrium of the heart and released in the circulation. ANP exhibits important functions in blood pressure and volume homeostasis, cardiac hypertrophy, and inhibition of cell proliferation. The binding of ANP to the cell surface guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA) activates its intrinsic guanylyl cyclase domain, causing production of the intracellular second messenger cGMP, and subsequently activating cGMP-dependent protein kinase (PKG). Although ANP is known to inhibit cell proliferation and promote apoptosis in numerous cell types, the signaling pathways responsible for the antimitogenic actions of ANP are not well understood. The objective of this study was to elucidate the role of the ANP-NPRA-PKG system in the inhibition of mitogen-activated protein kinases (MAPKs) and in cell growth and proliferation by studying effect of ANP on the activation of MAPKs and the downstream transcription factors cAMP response element binding protein (CREB) and activating protein-1 (AP-1) regulated by MAPKs. These studies have shown the role of the ANP-NPRA signaling system in regulating and inhibiting the proliferation of two types of cells: mouse mesangial cells (MMCs) and Leydig tumor cells (LEDs). We have delineated a pathway for this signaling system, demonstrating that ANP inhibits the activation of MAPKs and two specific proliferation-stimulating transcription factors downstream, CREB and AP-1, effects that were seen to be dependent on PKG and mediated through NPRA rather than through NPRC. These findings help to advance our understanding of the biochemical pathways through which ANP inhibits cell proliferation
