scholarly journals 45 years of cGMP research in Dictyostelium: Understanding the regulation and function of the cGMP pathway for cell movement and chemotaxis

2021 ◽  
pp. mbc.E21-04-0171
Author(s):  
Peter J.M. van Haastert ◽  
Ineke Keizer-Gunnink ◽  
Henderikus Pots ◽  
Claudia Ortiz-Mateos ◽  
Douwe Veltman ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Guanylyl Cyclase ◽  
Cell Movement ◽  
Soluble Guanylyl Cyclase ◽  
Leading Edge ◽  
Actin Binding ◽  
Myosin Filament ◽  
Cgmp Pathway ◽  
Cgmp Signaling ◽  
And Function

In Dictyostelium chemoattractants induce a fast cGMP response that mediates myosin filament formation in the rear of the cell. The major cGMP signaling pathway consists of a soluble guanylyl cyclase sGC, a cGMP-stimulated cGMP-specific phosphodiesterase and the cGMP-target protein GbpC. Here we combine published experiments with many unpublished experiments performed in the past 45 years on the regulation and function of the cGMP signaling pathway. The chemoattractants stimulate heterotrimeric Gαβγ and monomeric Ras proteins. A fraction of the soluble guanylyl cyclase sGC binds with high affinity to a limited number of membrane binding site, which is essential for sGC to become activated by Ras and Gα proteins. sGC can also bind to F-actin; binding to branched F-actin in pseudopods enhances basal sGC activity, whereas binding to parallel F-actin in the cortex reduces sGC activity. The cGMP pathway mediates cell polarity by inhibiting the rear: in unstimulated cells by sGC activity in the branched F-actin of pseudopods, in a shallow gradient by stimulated cGMP formation in pseudopods at the leading edge, and during cAMP oscillation to erase the previous polarity and establish a new polarity axis that aligns with the direction of the passing cAMP wave.

scholarly journals Cellular Distribution and Function of Soluble Guanylyl Cyclase in Rat Kidney and Liver

2001 ◽  
Vol 12 (11) ◽  
pp. 2209-2220 ◽  
Author(s):  
FRANZISKA THEILIG ◽  
MAGDALENA BOSTANJOGLO ◽  
HERMANN PAVENSTÄDT ◽  
CLEMENS GRUPP ◽  
GUDRUN HOLLAND ◽  
...  
Keyword(s):  
Guanylyl Cyclase ◽  
Mesangial Cells ◽  
Rat Kidney ◽  
Soluble Guanylyl Cyclase ◽  
No Donor ◽  
Ito Cells ◽  
Reverse Transcription Pcr ◽  
Cgmp Signaling ◽  
And Function

Abstract. Soluble guanylyl cyclase (sGC) catalyzes the biosynthesis of cGMP in response to binding of L-arginine-derived nitric oxide (NO). Functionally, the NO-sGC-cGMP signaling pathway in kidney and liver has been associated with regional hemodynamics and the regulation of glomerular parameters. The distribution of the ubiquitous sGC isoform α1β1 sGC was studied with a novel, highly specific antibody against the β1 subunit. In parallel, the presence of mRNA encoding both subunits was investigated by using in situ hybridization and reverse transcription-PCR assays. The NO-induced, sGC-dependent accumulation of cGMP in cytosolic extracts of tissues and cells was measured in vitro. Renal glomerular arterioles, including the renin-producing granular cells, mesangium, and descending vasa recta, as well as cortical and medullary interstitial fibroblasts, expressed sGC. Stimulation of isolated mesangial cells, renal fibroblasts, and hepatic Ito cells with a NO donor resulted in markedly increased cytosolic cGMP levels. This assessment of sGC expression and activity in vascular and interstitial cells of kidney and liver may have implications for understanding the role of local cGMP signaling cascades.

scholarly journals cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

2019 ◽  
Vol 393 (2) ◽  
pp. 287-302 ◽  
Author(s):  
Andreas Friebe ◽  
Peter Sandner ◽  
Achim Schmidtko
Keyword(s):  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Cell Types ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Therapeutic Implications ◽  
Cellular Effects ◽  
Recent Developments ◽  
And Function ◽  
Messenger Molecule

AbstractCyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. cGMP targets a variety of downstream effector molecules and, thus, elicits a very broad variety of cellular effects. Its production is triggered by stimulation of either soluble guanylyl cyclase (sGC) or particulate guanylyl cyclase (pGC); both enzymes exist in different isoforms. cGMP-induced effects are regulated by endogenous receptor ligands such as nitric oxide (NO) and natriuretic peptides (NPs). Depending on the distribution of sGC and pGC and the formation of ligands, this pathway regulates not only the cardiovascular system but also the kidney, lung, liver, and brain function; in addition, the cGMP pathway is involved in the pathogenesis of fibrosis, inflammation, or neurodegeneration and may also play a role in infectious diseases such as malaria. Moreover, new pharmacological approaches are being developed which target sGC- and pGC-dependent pathways for the treatment of various diseases. Therefore, it is of key interest to understand this pathway from scratch, beginning with the molecular basis of cGMP generation, the structure and function of both guanylyl cyclases and cGMP downstream targets; research efforts also focus on the subsequent signaling cascades, their potential crosstalk, and also the translational and, ultimately, the clinical implications of cGMP modulation. This review tries to summarize the contributions to the “9th International cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications” held in Mainz in 2019. Presented data will be discussed and extended also in light of recent landmark findings and ongoing activities in the field of preclinical and clinical cGMP research.

scholarly journals Hypertension reduces soluble guanylyl cyclase expression in the mouse aorta via the Notch signaling pathway

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Catarina Rippe ◽  
Baoyi Zhu ◽  
Katarzyna K. Krawczyk ◽  
Ed. Van Bavel ◽  
Sebastian Albinsson ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Notch Signaling Pathway ◽  
Mouse Aorta

scholarly journals Inhibition of Striatal Soluble Guanylyl Cyclase-cGMP Signaling Reverses Basal Ganglia Dysfunction and Akinesia in Experimental Parkinsonism

PLoS ONE ◽  
2011 ◽  
Vol 6 (11) ◽  
pp. e27187 ◽  
Author(s):  
Kuei Y. Tseng ◽  
Adriana Caballero ◽  
Alexander Dec ◽  
Daryn K. Cass ◽  
Natalie Simak ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Experimental Parkinsonism ◽  
Cgmp Signaling

scholarly journals Rear-polarized Wnt5a-receptor-actin-myosin-polarity (WRAMP) structures promote the speed and persistence of directional cell migration

2017 ◽  
Vol 28 (14) ◽  
pp. 1924-1936 ◽  
Author(s):  
Mary Katherine Connacher ◽  
Jian Wei Tay ◽  
Natalie G. Ahn
Keyword(s):  
Cell Migration ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Cell Movement ◽  
Leading Edge ◽  
Cellular Mechanism ◽  
Directional Movement ◽  
New Directions ◽  
And Function ◽  
Directional Cell Migration

In contrast to events at the cell leading edge, rear-polarized mechanisms that control directional cell migration are poorly defined. Previous work described a new intracellular complex, the Wnt5a-receptor-actomyosin polarity (WRAMP) structure, which coordinates the polarized localization of MCAM, actin, and myosin IIB in a Wnt5a-induced manner. However, the polarity and function for the WRAMP structure during cell movement were not determined. Here we characterize WRAMP structures during extended cell migration using live-cell imaging. The results demonstrate that cells undergoing prolonged migration show WRAMP structures stably polarized at the rear, where they are strongly associated with enhanced speed and persistence of directional movement. Strikingly, WRAMP structures form transiently, with cells displaying directional persistence during periods when they are present and cells changing directions randomly when they are absent. Cells appear to pause locomotion when WRAMP structures disassemble and then migrate in new directions after reassembly at a different location, which forms the new rear. We conclude that WRAMP structures represent a rear-directed cellular mechanism to control directional migration and that their ability to form dynamically within cells may control changes in direction during extended migration.

scholarly journals Cancer-associated mutations in the protrusion-targeting region of p190RhoGAP impact tumor cell migration

2016 ◽  
Vol 214 (7) ◽  
pp. 859-873 ◽  
Author(s):  
Fabien Binamé ◽  
Aurélien Bidaud-Meynard ◽  
Laure Magnan ◽  
Léo Piquet ◽  
Bertille Montibus ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Leading Edge ◽  
Negative Regulator ◽  
Actin Binding ◽  
Tumor Cell Migration ◽  
Spatiotemporal Regulation ◽  
Localization Sequence ◽  
Actin Protrusions ◽  
And Function

Spatiotemporal regulation of RhoGTPases such as RhoA is required at the cell leading edge to achieve cell migration. p190RhoGAP (p190A) is the main negative regulator of RhoA and localizes to membrane protrusions, where its GTPase-activating protein (GAP) activity is required for directional migration. In this study, we investigated the molecular processes responsible for p190A targeting to actin protrusions. By analyzing the subcellular localization of truncated versions of p190A in hepatocellular carcinoma cells, we identified a novel functional p190A domain: the protrusion localization sequence (PLS) necessary and sufficient for p190A targeting to leading edges. Interestingly, the PLS is also required for the negative regulation of p190A RhoGAP activity. Further, we show that the F-actin binding protein cortactin binds the PLS and is required for p190A targeting to protrusions. Lastly, we demonstrate that cancer-associated mutations in PLS affect p190A localization and function, as well as tumor cell migration. Altogether, our data unveil a new mechanism of regulation of p190A in migrating tumor cells.

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