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cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (20 November 2023) | Viewed by 17131

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Prof. Dr. Jens Schlossmann

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Pharmakologie und Toxikologie, Institut für Pharmazie, Universitätsstr. 31, 93040 Regensburg, Germany
Interests: cGMP; signaling proteins; signal transduction pathways; kinases
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Special Issue Information

Dear Colleagues,

Cellular and tissue signaling by cGMP is an expanding field which comprises molecular function and (patho)physiology in various organ systems. cGMP synthesis, degradation, and function are modulated by a variety of signaling proteins and signal transduction pathways. Stuctural, biochemical, and (patho)physiological aspects have been strongly developed in the last decade, e.g., regarding cardiovascular, renal, pulmonary, gastrointestinal, and neuronal function. Dysregulation of cGMP generators (guanylyl cyclases), modulators (phosphodiesterases), and signaling molecules (e.g., kinases/substrates, channels) has been elucidated as the cause of pathophysiological processes and diseases. Pharmacological approaches have been propagated into pharmacological treatments including hypertension, cardiovascular, and gastrointestinal diseases. Therefore, the molecular and functional understanding of the diverse cGMP generators, signalling proteins, scaffolds, and signal transduction pathways is fundamental for insight into their (patho)physiological processes. The scope of the Special Issue is to summarize and enlarge the knowledge of these signaling processes and networks in diverse cells/tissues and to link it to (patho)physiological and pharmacological functions.

Therefore, authors are invited to submit original research and review articles which address the progress and current standing of cGMP signaling.

Topics include but are not limited to:

Identification of and new molecular and functional aspects in cGMP-signaling molecules and pathways;
Analysis of cGMP-signal generation, modulation, recognition, and/or its transduction into (patho)physiological responses and/or pharmacologcal approaches;
Techniques for the analysis and identification of cGMP signalling molecules, scaffolds, pathways, and networks.

Prof. Dr. Jens Schlossmann
Guest Editor

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Keywords

cGMP
signaling proteins
signal transduction pathways
scaffolds
nitric oxide
natriuretic peptides
guanylyl cyclases
kinases
phosphodiesterases
channels
(patho)physiology
pharmacology

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cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects in International Journal of Molecular Sciences (8 articles)

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Research

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21 pages, 5906 KiB

Open AccessArticle

The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration

by Arianna Tolone, Wadood Haq, Alexandra Fachinger, Akanksha Roy, Sandeep Kesh, Andreas Rentsch, Sophie Wucherpfennig, Yu Zhu, John Groten, Frank Schwede, Tushar Tomar, Friedrich W. Herberg, Vasilica Nache and François Paquet-Durand

Int. J. Mol. Sci. 2023, 24(20), 15277; https://doi.org/10.3390/ijms242015277 - 17 Oct 2023

Cited by 4 | Viewed by 2375

Abstract

Hereditary retinal degeneration (RD) is often associated with excessive cGMP signalling in photoreceptors. Previous research has shown that inhibition of cGMP-dependent protein kinase G (PKG) can reduce photoreceptor loss in two different RD animal models. In this study, we identified a PKG inhibitor, the cGMP analogue CN238, which preserved photoreceptor viability and functionality in rd1 and rd10 mutant mice. Surprisingly, in explanted retinae, CN238 also protected retinal ganglion cells from axotomy-induced retrograde degeneration and preserved their functionality. Furthermore, kinase activity-dependent protein phosphorylation of the PKG target Kv1.6 was reduced in CN238-treated rd10 retinal explants. Ca²⁺-imaging on rd10 acute retinal explants revealed delayed retinal ganglion cell repolarization with CN238 treatment, suggesting a PKG-dependent modulation of Kv1-channels. Together, these results highlight the strong neuroprotective capacity of PKG inhibitors for both photoreceptors and retinal ganglion cells, illustrating their broad potential for the treatment of retinal diseases and possibly neurodegenerative diseases in general. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects 2.0)

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20 pages, 7132 KiB

Open AccessArticle

The sGC Activator Runcaciguat Has Kidney Protective Effects and Prevents a Decline of Kidney Function in ZSF1 Rats

by Jan R. Kraehling, Agnes Benardeau, Tibor Schomber, Laura Popp, Julia Vienenkoetter, Heidrun Ellinger-Ziegelbauer, Mira Pavkovic, Elke Hartmann, Krystyna Siudak, Alexius Freyberger, Ina Hagelschuer, Ilka Mathar, Joerg Hueser, Michael G. Hahn, Volker Geiss, Frank Eitner and Peter Sandner

Int. J. Mol. Sci. 2023, 24(17), 13226; https://doi.org/10.3390/ijms241713226 - 25 Aug 2023

Cited by 2 | Viewed by 1914

Abstract

Chronic kidney disease (CKD) progression is associated with persisting oxidative stress, which impairs the NO-sGC-cGMP signaling cascade through the formation of oxidized and heme-free apo-sGC that cannot be activated by NO. Runcaciguat (BAY 1101042) is a novel, potent, and selective sGC activator that binds and activates oxidized and heme-free sGC and thereby restores NO-sGC-cGMP signaling under oxidative stress. Therefore, runcaciguat might represent a very effective treatment option for CKD/DKD. The potential kidney-protective effects of runcaciguat were investigated in ZSF1 rats as a model of CKD/DKD, characterized by hypertension, hyperglycemia, obesity, and insulin resistance. ZSF1 rats were treated daily orally for up to 12 weeks with runcaciguat (1, 3, 10 mg/kg/bid) or placebo. The study endpoints were proteinuria, kidney histopathology, plasma, urinary biomarkers of kidney damage, and gene expression profiling to gain information about relevant pathways affected by runcaciguat. Furthermore, oxidative stress was compared in the ZSF1 rat kidney with kidney samples from DKD patients. Within the duration of the 12-week treatment study, kidney function was significantly decreased in obese ZSF1 rats, indicated by a 20-fold increase in proteinuria, compared to lean ZSF1 rats. Runcaciguat dose-dependently and significantly attenuated the development of proteinuria in ZSF1 rats with reduced uPCR at the end of the study by −19%, −54%, and −70% at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo treatment. Additionally, average blood glucose levels measured as HbA1C, triglycerides, and cholesterol were increased by five times, twenty times, and four times, respectively, in obese ZSF1 compared to lean rats. In obese ZSF1 rats, runcaciguat reduced HbA1c levels by −8%, −34%, and −76%, triglycerides by −42%, −55%, and −71%, and cholesterol by −16%, −17%, and −34%, at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo. Concomitantly, runcaciguat also reduced kidney weights, morphological kidney damage, and urinary and plasma biomarkers of kidney damage. Beneficial effects were accompanied by changes in gene expression that indicate reduced fibrosis and inflammation and suggest improved endothelial stabilization. In summary, the sGC activator runcaciguat significantly prevented a decline in kidney function in a DKD rat model that mimics common comorbidities and conditions of oxidative stress of CKD patients. Thus, runcaciguat represents a promising treatment option for CKD patients, which is in line with recent phase 2 clinical study data, where runcaciguat showed promising efficacy in CKD patients (NCT04507061). Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects 2.0)

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16 pages, 14805 KiB

Open AccessArticle

Anti-Fibrotic and Anti-Inflammatory Role of NO-Sensitive Guanylyl Cyclase in Murine Lung

by Nils Englert, Philipp Burkard, Annemarie Aue, Andreas Rosenwald, Bernhard Nieswandt and Andreas Friebe

Int. J. Mol. Sci. 2023, 24(14), 11661; https://doi.org/10.3390/ijms241411661 - 19 Jul 2023

Cited by 1 | Viewed by 1358

Abstract

Pulmonary fibrosis is a chronic and progressive disease with limited therapeutic options. Nitric oxide (NO) is suggested to reduce the progression of pulmonary fibrosis via NO-sensitive guanylyl cyclase (NO-GC). The exact effects of NO-GC during pulmonary fibrosis are still elusive. Here, we used a NO-GC knockout mouse (GCKO) and examined fibrosis and inflammation after bleomycin treatment. Compared to wildtype (WT), GCKO mice showed an increased fibrotic reaction, as myofibroblast occurrence (p = 0.0007), collagen content (p = 0.0006), and mortality (p = 0.0009) were significantly increased. After fibrosis induction, lymphocyte accumulations were observed in the lungs of GCKO but not in WT littermates. In addition, the total number of immune cells, specifically lymphocytes (p = <0.0001) and neutrophils (p = 0.0047), were significantly higher in the bronchoalveolar lavage fluid (BALF) of GCKO animals compared to WT, indicating an increased inflammatory response in the absence of NO-GC. The pronounced fibrotic response in GCKO mice was paralleled by significantly increased levels of transforming growth factor β (TGFβ) in BALF (p = 0.0207), which correlated with the total number of immune cells. Taken together, our data show the effect of NO-GC deletion in the pathology of lung fibrosis and the effect on immune cells in BALF. In summary, our results show that NO-GC has anti-inflammatory and anti-fibrotic properties in the murine lung, very likely by attenuating TGFβ-mediated effects. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects 2.0)

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21 pages, 3739 KiB

Open AccessArticle

Characterizing the Protein Isoforms of foraging (for), the PKGI Ortholog in Drosophila melanogaster

by Oscar E. Vasquez, Aaron M. Allen, Anthony K.-C. So, Quynh H. Nguyen, Henry M. Krause, Joel D. Levine and Marla B. Sokolowski

Int. J. Mol. Sci. 2023, 24(12), 10219; https://doi.org/10.3390/ijms241210219 - 16 Jun 2023

Viewed by 1625

Abstract

The foraging (for) gene of Drosophila melanogaster encodes a cGMP-dependent protein kinase (PKG), which is a major effector of the cGMP signaling pathway involved in the regulation of behaviour and metabolic traits. Despite being well studied at the transcript level, little is known about the for gene at the protein level. Here, we provide a detailed characterization of the for gene protein (FOR) products and present new tools for their study, including five isoform-specific antibodies and a transgenic strain that carries an HA-labelled for allele (for^BAC::HA). Our results showed that multiple FOR isoforms were expressed in the larval and adult stages of D. melanogaster and that the majority of whole-body FOR expression arises from three (P1, P1α, and P3) of eight putative protein isoforms. We found that FOR expression differed between the larval and adult stages and between the dissected larval organs we analyzed, which included the central nervous system (CNS), fat body, carcass, and intestine. Moreover, we showed that the FOR expression differed between two allelic variants of the for gene, namely, for^s (sitter) and for^R (rover), that are known to differ in many food-related traits. Together, our in vivo identification of FOR isoforms and the existence of temporal, spatial, and genetic differences in their expression lay the groundwork for determining their functional significance. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects 2.0)

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16 pages, 2568 KiB

Open AccessArticle

A Non-Systemic Phosphodiesterase-5 Inhibitor Suppresses Colon Proliferation in Mice

by Avelina Lee, Iryna Lebedyeva, Wenbo Zhi, Vani Senthil, Herjot Cheema, Michael W. Brands, Weston Bush, Nevin A. Lambert, Madeline Snipes and Darren D. Browning

Int. J. Mol. Sci. 2023, 24(11), 9397; https://doi.org/10.3390/ijms24119397 - 28 May 2023

Cited by 1 | Viewed by 1810

Abstract

Phosphodiesterase-5 inhibitors (PDE5i) are under investigation for repurposing for colon cancer prevention. A drawback to conventional PDE5i are their side-effects and drug–drug interactions. We designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity, and measured its entry into the circulation and effects on colon epithelium. This modification did not affect pharmacology as malonyl-sildenafil had a similar IC₅₀ to sildenafil but exhibited an almost 20-fold reduced EC₅₀ for increasing cellular cGMP. Using an LC-MS/MS approach, malonyl-sildenafil was negligible in mouse plasma after oral administration but was detected at high levels in the feces. No bioactive metabolites of malonyl-sildenafil were detected in the circulation by measuring interactions with isosorbide mononitrate. The treatment of mice with malonyl-sildenafil in the drinking water resulted in a suppression of proliferation in the colon epithelium that is consistent with results previously published for mice treated with PDE5i. A carboxylic-acid-containing analog of sildenafil prohibits the systemic delivery of the compound but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generating a first-in-class drug for colon cancer chemoprevention. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects 2.0)

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18 pages, 2725 KiB

Open AccessArticle

Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation

by Xiao Ma, Seethalakshmi R. Iyer, Xiaoyu Ma, Shawn H. Reginauld, Yang Chen, Shuchong Pan, Ye Zheng, Dante G. Moroni, Yue Yu, Lianwen Zhang, Valentina Cannone, Horng H. Chen, Carlos M. Ferrario, S. Jeson Sangaralingham and John C. Burnett, Jr.

Int. J. Mol. Sci. 2023, 24(10), 8547; https://doi.org/10.3390/ijms24108547 - 10 May 2023

Cited by 4 | Viewed by 2054

Abstract

The natriuretic peptide system (NPS) and renin-angiotensin-aldosterone system (RAAS) function oppositely at multiple levels. While it has long been suspected that angiotensin II (ANGII) may directly suppress NPS activity, no clear evidence to date supports this notion. This study was designed to systematically investigate ANGII–NPS interaction in humans, in vivo, and in vitro. Circulating atrial, b-type, and c-type natriuretic peptides (ANP, BNP, CNP), cyclic guanosine monophosphate (cGMP), and ANGII were simultaneously investigated in 128 human subjects. Prompted hypothesis was validated in vivo to determine the influence of ANGII on ANP actions. The underlying mechanisms were further explored via in vitro approaches. In humans, ANGII demonstrated an inverse relationship with ANP, BNP, and cGMP. In regression models predicting cGMP, adding ANGII levels and the interaction term between ANGII and natriuretic peptides increased the predictive accuracy of the base models constructed with either ANP or BNP, but not CNP. Importantly, stratified correlation analysis further revealed a positive association between cGMP and ANP or BNP only in subjects with low, but not high, ANGII levels. In rats, co-infusion of ANGII even at a physiological dose attenuated cGMP generation mediated by ANP infusion. In vitro, we found the suppressive effect of ANGII on ANP-stimulated cGMP requires the presence of ANGII type-1 (AT₁) receptor and mechanistically involves protein kinase C (PKC), as this suppression can be substantially rescued by either valsartan (AT₁ blocker) or Go6983 (PKC inhibitor). Using surface plasmon resonance (SPR), we showed ANGII has low binding affinity to the guanylyl cyclase A (GC-A) receptor compared to ANP or BNP. Our study reveals ANGII is a natural suppressor for the cGMP-generating action of GC-A via AT₁/PKC dependent manner and highlights the importance of dual-targeting RAAS and NPS in maximizing beneficial properties of natriuretic peptides in cardiovascular protection. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects 2.0)

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Review

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19 pages, 1333 KiB

Open AccessReview

cGMP Signaling in Photoreceptor Degeneration

by Shujuan Li, Hongwei Ma, Fan Yang and Xiqin Ding

Int. J. Mol. Sci. 2023, 24(13), 11200; https://doi.org/10.3390/ijms241311200 - 7 Jul 2023

Cited by 5 | Viewed by 3409

Abstract

Photoreceptors in the retina are highly specialized neurons with photosensitive molecules in the outer segment that transform light into chemical and electrical signals, and these signals are ultimately relayed to the visual cortex in the brain to form vision. Photoreceptors are composed of rods and cones. Rods are responsible for dim light vision, whereas cones are responsible for bright light, color vision, and visual acuity. Photoreceptors undergo progressive degeneration over time in many hereditary and age-related retinal diseases. Despite the remarkable heterogeneity of disease-causing genes, environmental factors, and pathogenesis, the progressive death of rod and cone photoreceptors ultimately leads to loss of vision/blindness. There are currently no treatments available for retinal degeneration. Cyclic guanosine 3′, 5′-monophosphate (cGMP) plays a pivotal role in phototransduction. cGMP governs the cyclic nucleotide-gated (CNG) channels on the plasma membrane of the photoreceptor outer segments, thereby regulating membrane potential and signal transmission. By gating the CNG channels, cGMP regulates cellular Ca²⁺ homeostasis and signal transduction. As a second messenger, cGMP activates the cGMP-dependent protein kinase G (PKG), which regulates numerous targets/cellular events. The dysregulation of cGMP signaling is observed in varieties of photoreceptor/retinal degenerative diseases. Abnormally elevated cGMP signaling interferes with various cellular events, which ultimately leads to photoreceptor degeneration. In line with this, strategies to reduce cellular cGMP signaling result in photoreceptor protection in mouse models of retinal degeneration. The potential mechanisms underlying cGMP signaling-induced photoreceptor degeneration involve the activation of PKG and impaired Ca²⁺ homeostasis/Ca²⁺ overload, resulting from overactivation of the CNG channels, as well as the subsequent activation of the downstream cellular stress/death pathways. Thus, targeting the cellular cGMP/PKG signaling and the Ca²⁺-regulating pathways represents a significant strategy for photoreceptor protection in retinal degenerative diseases. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects 2.0)

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22 pages, 1199 KiB

Open AccessReview

Novel Functional Features of cGMP Substrate Proteins IRAG1 and IRAG2

by Sally Prüschenk, Michael Majer and Jens Schlossmann

Int. J. Mol. Sci. 2023, 24(12), 9837; https://doi.org/10.3390/ijms24129837 - 7 Jun 2023

Cited by 1 | Viewed by 1762

Abstract

The inositol triphosphate-associated proteins IRAG1 and IRAG2 are cGMP kinase substrate proteins that regulate intracellular Ca²⁺. Previously, IRAG1 was discovered as a 125 kDa membrane protein at the endoplasmic reticulum, which is associated with the intracellular Ca²⁺ channel IP₃R-I and the PKGIβ and inhibits IP₃R-I upon PKGIβ-mediated phosphorylation. IRAG2 is a 75 kDa membrane protein homolog of IRAG1 and was recently also determined as a PKGI substrate. Several (patho-)physiological functions of IRAG1 and IRAG2 were meanwhile elucidated in a variety of human and murine tissues, e.g., of IRAG1 in various smooth muscles, heart, platelets, and other blood cells, of IRAG2 in the pancreas, heart, platelets, and taste cells. Hence, lack of IRAG1 or IRAG2 leads to diverse phenotypes in these organs, e.g., smooth muscle and platelet disorders or secretory deficiency, respectively. This review aims to highlight the recent research regarding these two regulatory proteins to envision their molecular and (patho-)physiological tasks and to unravel their functional interplay as possible (patho-)physiological counterparts. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects 2.0)

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