Review
Biochemistry & Molecular Biology
Gang Wu, Iraida Sharina, Emil Martin
Summary: Nitric oxide (NO), carbon monoxide (CO), oxygen (O-2), and hydrogen sulfide (H2S) are gaseous molecules that play important roles in the physiology and pathophysiology of eukaryotes. Soluble guanylyl cyclase (sGC), a hemoprotein, acts as a sensor and transducer for these gases, as well as a transporter.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Cheng Zhong, Minze Xu, Senguel Boral, Holger Summer, Falk-Bach Lichtenberger, Cem Erdogan, Maik Gollasch, Stefan Golz, Pontus B. Persson, Johanna Schleifenbaum, Andreas Patzak, Pratik H. Khedkar
Summary: Aging affects the downstream signaling of the endothelial nitric oxide system in vascular smooth muscle, leading to compromised vasorelaxation even in the absence of histopathological alterations. The reduced expression of sGC and PDE5 may contribute to the impaired vasorelaxation in aged vessels.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Endocrinology & Metabolism
Hari Prasad, John Kandam Kulathu Mathew, Sandhya S. Visweswariah
Summary: This review highlights the importance of Receptor Guanylyl Cyclase C (GC-C) in regulating intestinal fluid and ion homeostasis, and its causal link to intestinal inflammation, dysbiosis, and tumorigenesis. The GC-C signaling pathway plays a role in extra gastrointestinal functions such as appetite control, energy expenditure, visceral nociception, and behavioral processes. Recent research has also uncovered the involvement of GC-C in the ion-microbiome-immune axis in inflammatory bowel disease and suggests potential therapeutic strategies.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Maryam Alapa, Chuanlong Cui, Ping Shu, Hong Li, Vlad Kholodovych, Annie Beuve
Summary: The study found that redox modifications play a crucial role in NO activation of GC1, with NO-stimulated GC1 containing more bound Cys, potentially disulfide bonds. Mass spectrometry identified ten oxidized and two reduced Cys in NO-stimulated GC1, and computational modeling narrowed down potential Cys candidates involved in disulfide bonds to Cys489 and Cys571. Mutational studies confirmed the involvement of Cys489 and Cys571 in GC1's response to NO, potentially as a thiol/disulfide switch.
FREE RADICAL BIOLOGY AND MEDICINE
(2021)
Article
Physiology
Malte Verheyen, Michelle Puschkarow, Stefanie Gnipp, Doris Koesling, Marcus Peters, Evanthia Mergia
Summary: In this study, we investigated the role of NO-GC isoforms in respiration by measuring lung function parameters of isoform-specific knockout mice. Our findings suggest that NO-GC1-derived cGMP plays a significant role in regulating airway tone, while NO-GC2 affects tissue elasticity and airway reactivity.
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Yueksel Korkmaz, Markus Plomann, Behrus Puladi, Ayseguel Demirbas, Wilhelm Bloch, James Deschner
Summary: The binding of nitric oxide to heme in the beta(1) subunit of soluble guanylyl cyclase activates the enzyme and increases cGMP production. Exogenous NO can inhibit mast cell degranulation via NO-cGMP signaling. However, oxidative or nitrosative stress can make the enzyme insensitive to NO. The study investigates the presence of mast cells and the expression of the alpha(1) and beta(1) subunits of soluble guanylyl cyclase in healthy and inflamed dental pulp.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Kevin M. Gayler, Jeremy M. Quintana, Jordan Mattke, Michael A. Plunk, Jessica H. Kostyo, Johann W. Karunananthan, Harold Nguyen, Mina Shuda, Liam D. Ferreira, Hannah Baker, Alexandra L. Stinchcomb, Iraida Sharina, Robert R. Kane, Emil Martin
Summary: Previous studies have shown that the anti-hyperlipidemic drug gemfibrozil can activate the NO receptor soluble guanylyl cyclase independently of NO and heme. New gemfibrozil derivatives were synthesized and evaluated for sGC activation, identifying positions in gemfibrozil's structure that are important for activation. Compounds 7c and 15b were found to be more potent activators of purified sGC's cGMP-forming activity compared to gemfibrozil, showing enhanced relaxation of preconstricted mouse thoracic aorta rings. These findings provide insights for further optimization of sGC activators based on the gemfibrozil scaffold.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cardiac & Cardiovascular Systems
Joseph C. Galley, Megan P. Miller, Subramaniam Sanker, Mingjun Liu, Iraida Sharina, Emil Martin, Delphine Gomez, Adam C. Straub
Summary: This study identifies Forkhead box subclass O protein 4 (FoxO4) as a key transcriptional regulator of GUCY1B3 expression, coding for sGC13 protein in human and animal smooth muscle cells (SMCs). This discovery may have important implications for future antihypertensive and vasodilatory therapies targeting NO production, sGC, or FoxO transcription factors.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
(2022)
Editorial Material
Microbiology
James M. Fleckenstein, Jacob P. Bitoun
Summary: The study shows how bats have evolutionarily maintained fluid homeostasis signaling while avoiding the pathogenic effects of ST.
CELL HOST & MICROBE
(2021)
Article
Pharmacology & Pharmacy
Miguel A. A. Olivencia, Leticia Gil de Biedma-Elduayen, Pablo Gimenez-Gomez, Bianca Barreira, Argentina Fernandez, Javier Angulo, Maria Isabel Colado, Esther O'Shea, Francisco Perez-Vizcaino
Summary: This study investigates the relationship between alcohol abuse and erectile dysfunction (ED), finding that alterations in soluble guanylyl cyclase (sGC) may contribute to ED caused by alcoholism. The results show that alcohol abuse reduces the relaxant response of the corpora cavernosa (CC) but enhances the response to sGC activators, while also increasing reactive oxygen species and protein expression of CYP2E1 and NOX2. These findings suggest that sGC activators may be effective in treating ED associated with alcoholism.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Iraida Sharina, Karina Lezgyieva, Yekaterina Krutsenko, Emil Martin
Summary: This study characterized a rare sGC variant with reduced cGMP-forming activity, high susceptibility to oxidative stress, and diminished protein stability. These deficiencies contribute to the severity of moyamoya disease and achalasia symptoms in carriers of this variant.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ellis Nelissen, Elentina K. Argyrousi, Nick P. Van Goethem, Fuqiang Zhao, Catherine D. G. Hines, Gayathri Swaminath, Michael Gerisch, Joerg Hueser, Peter Sandner, Jos Prickaerts
Summary: The study found that the sGC stimulator vericiguat can enhance long-term memory by increasing hippocampal plasticity and promoting the translocation of oc-AMPA receptors to the cell membrane, while having no effect on blood pressure and cerebral blood volume. Stimulation of sGC may provide a new therapeutic strategy for treating VCI.
Article
Health Care Sciences & Services
Gao Jing, Zhang Xia, Quan Lei
Summary: This study aims to develop gene therapy targeting the NO-sGC-cGMP pathway to overcome cytotoxicity and tolerance caused by prolonged use of NO donors and insufficient PDE inhibitors. Lentivirus vectors were constructed to enhance cGMP synthesis and degrade PDE5A, resulting in increased sGC activity and elevated cGMP level in HEK293 cells. Co-expression of exogenous subunits of soluble guanylyl cyclase and PDE5A shRNA alleviated feedback up-regulation and showed no obvious cytotoxicity.
TECHNOLOGY AND HEALTH CARE
(2023)
Article
Cell Biology
Mamta P. Sumi, Arnab Ghosh
Summary: The maturation of hemeprotein is essential for cellular function, and studies have shown that Hsp90 plays a key role in driving heme maturation. It connects globin maturation to the NO-sGC signal pathway, which is significant for therapeutic intervention, particularly in aggressive cancer cells. The combination of sGC activators/stimulators and specific Hsp90 inhibitors may provide better therapeutic options.
Article
Endocrinology & Metabolism
Brandon M. Wagner, Jerid W. Robinson, Timothy C. R. Prickett, Eric A. Espiner, Sundeep Khosla, Dana Gaddy, Larry J. Suva, Lincoln R. Potter
Summary: C-type natriuretic peptide (CNP) activates guanylyl cyclase-B (GC-B) to catalyze the synthesis of cGMP, which affects bone length and mass. GC-B mutant mice with increased CNP-dependent GC-B activity show increased bone length, mass, and strength. However, the mechanism by which GC-B increases bone mass remains unknown.
CALCIFIED TISSUE INTERNATIONAL
(2022)
Article
Physiology
Kulwant S. Aulak, Sami Al Abdi, Ling Li, Jack S. Crabb, Arnab Ghosh, Belinda Willard, Dennis J. Stuehr, John W. Crabb, Raed A. Dweik, Adriano R. Tonelli
Summary: Idiopathic pulmonary arterial hypertension (IPAH) is a rapidly progressive disease with great heterogeneity in treatment response and systemic involvement, despite most of its pathology being observed in the lung. Platelets from IPAH patients exhibit characteristic metabolic shifts and activation defects, as well as abnormalities in prostacyclin and nitric oxide pathways. These findings suggest potential targets for therapy, with variations in soluble guanylate cyclase levels showing implications for personalized treatment in IPAH patients. Platelets may provide informative mechanistic insights ex vivo to guide therapeutic decisions in IPAH.
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Arnab Ghosh, Cynthia J. Koziol-White, William F. Jester, Serpil C. Erzurum, Kewal Asosingh, Reynold A. Panettieri, Dennis J. Stuehr
Summary: The study revealed that severe asthmatics have inherent defects in sGC in their airway smooth muscle, leading to impaired NO-sGC-cGMP signaling. This dysfunction is associated with changes in cell redox enzymes that impact sGC maturation and function.
Article
Pharmacology & Pharmacy
Yue Dai, Dennis J. Stuehr
Summary: The study investigated the changes that occur to sGC during its inactivation in cells using HEK293 cells expressing sGC proteins, where oxidative or nitrosative inactivation of sGC involved sGC heterodimer dissociation and rearrangement of the sGC beta protein partners without any haem loss from sGC beta. Understanding these changes may direct strategies to preserve or recover NO-dependent cGMP signaling in health and disease.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Blair Tupta, Eric Stuehr, Mamta P. Sumi, Elizabeth A. Sweeny, Brandon Smith, Dennis J. Stuehr, Arnab Ghosh
Summary: This study reveals the important role of GAPDH in the maturation of myoglobin and hemoglobins by regulating the formation of sGC alpha1 beta1 heterodimer, iron provision, and the expression of GAPDH. These findings provide insights into the mechanisms of heme-maturation in globins.
Article
Biochemistry & Molecular Biology
Daniel L. Drew, Tanbi Ahammad, Rachel A. Serafin, Indra D. Sahu, Rasal H. Khan, Emily Faul, Robert M. McCarrick, Gary A. Lorigan
Summary: Advances have been made in detecting local secondary structures of membrane proteins using electron paramagnetic resonance (EPR) methods. A three pulsed electron spin echo envelope modulation (ESEEM) approach was used to determine the local helical secondary structure of the small hole forming membrane protein, S-21 pinholin. Circular dichroism (CD) spectroscopy was also used to study the overall global helical structure of S-21 pinholin.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2022)
Article
Biochemistry & Molecular Biology
Rosemary Westcott, Natalie Chung, Arnab Ghosh, Lisa Ferguson, William Bingaman, Imad M. Najm, Chaitali Ghosh
Summary: This study reveals that the different isoforms of glucocorticoid receptor (GR) at the blood-brain barrier (BBB) play important roles in the pathogenesis of drug-resistant epilepsy with focal cortical dysplasia (FCD). The expression of GR beta is upregulated in dysplastic brain tissue and is associated with age and gender. The findings suggest that GR beta could serve as a potential biomarker and therapeutic target for dysplasia in epilepsy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Mamta P. Sumi, Arnab Ghosh
Summary: The maturation of hemeprotein is essential for cellular function, and studies have shown that Hsp90 plays a key role in driving heme maturation. It connects globin maturation to the NO-sGC signal pathway, which is significant for therapeutic intervention, particularly in aggressive cancer cells. The combination of sGC activators/stimulators and specific Hsp90 inhibitors may provide better therapeutic options.
Article
Biochemistry & Molecular Biology
Yue Dai, Angela S. Fleischhacker, Liu Liu, Sara Fayad, Amanda L. Gunawan, Dennis J. Stuehr, Stephen W. Ragsdale
Summary: GAPDH is involved in heme delivery to HO2, maintaining cellular heme homeostasis.
BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Arnab Ghosh, Mamta P. Sumi, Blair Tupta, Toshihiro Okamoto, Kulwant Aulak, Masato Tsutsui, Hiroaki Shimokawa, Serpil C. Erzurum, Dennis J. Stuehr
Summary: Low doses of NO have a dual effect on the maturation of key hemeproteins, acting both to promote and inhibit heme-insertion, while high NO doses inhibit heme-insertion. This phenomenon is observed in soluble guanylyl cyclase, globins, nitric oxide synthases, and Myeloperoxidase. The effects of low NO on hemeprotein maturation require the presence of the NO-sGC-cGMP signal pathway.
Article
Cell Biology
Mamta P. Sumi, Blair Tupta, Arnab Ghosh
Summary: NO acts as a vasodilator and triggers heme insertion into hemoglobin and myoglobin. This process is dose-dependent, with better efficiency at lower doses. It involves both transcriptional and translational events.
Article
Pharmacology & Pharmacy
Yue Dai, Dennis J. Stuehr
Summary: The study found that BAY58 can activate different forms of sGC in cells. It was observed that BAY58 can rapidly induce cGMP production in cells with heme-free sGC heterodimer, while it requires a longer time to activate cGMP production in cells with heme-containing sGC. These findings provide insight into the mechanism of BAY58 activation of sGC in both health and disease.
MOLECULAR PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mamta P. Sumi, Blair Tupta, Sanjoy Roychowdhury, Suzy Comhair, Kewal Asosingh, Dennis J. Stuehr, Serpil C. Erzurum, Arnab Ghosh
Summary: This study discovered that hemoglobin in lung epithelial cells can protect soluble guanylyl cyclase in smooth muscles from excessive nitric oxide. However, in patients with asthma or chronic obstructive pulmonary disease, lung epithelial hemoglobin may be unable to scavenge nitric oxide due to a lack of heme.