User:QuantumProtein/Cyclic guanosine monophosphate

All changes for cGMP will be in this sandbox.

Here are a list of sources I am planning on using

Review Articles:

https://pmc.ncbi.nlm.nih.gov/articles/PMC3263465/

https://pmc.ncbi.nlm.nih.gov/articles/PMC1369255/

Primary Article:

https://www.jacc.org/doi/full/10.1016/j.jacc.2020.08.031

https://www.ahajournals.org/doi/full/10.1161/JAHA.119.013966

https://pmc.ncbi.nlm.nih.gov/articles/PMC8090939/

Image:

Ball and Stick model of the cyclic guanosine monophosphate molecule, also known as cGMP. Colour code:   Carbon, C: black   Hydrogen, H: white   Oxygen, O: red   Nitrogen, N: blue   Phosphorus, P: orange. Image generated in Molview

I want to change the current image that uses the space filling model to a ball and stick, this will allow for someone to better see the structure.

Also create a better version of cGMP protein pathway Map that better explains it with respect to physiology.

History

Cyclic guanosine monophosphate (cGMP) research began in the 1960s when cGMP and cyclic adenosine monophosphate (cAMP) were first identified as natural cellular components (Beavo & Brunton, 2002). ADD SOURCE The discovery of cAMP led to the formulation of the second-messenger concept in hormone signaling by Earl W. Sutherland, who received the Nobel Prize in Physiology or Medicine in 1971 for his contributions. This award sparked extensive research into cAMP, while cGMP initially received less attention, with its biological functions largely unknown until the 1980s. During this period, two pivotal discoveries highlighted cGMP’s role in cellular signaling: atrial natriuretic peptide (ANP) was found to stimulate cGMP synthesis through the particulate guanylyl cyclase (pGC) receptor, and nitric oxide (NO), identified as the endothelium-derived relaxing factor, was shown to activate soluble guanylyl cyclase (sGC), producing cGMP to mediate vasorelaxation in smooth muscle cells. As further components of the cGMP pathway were identified, such as cGMP-hydrolyzing phosphodiesterases (PDEs) and cGMP-binding proteins, researchers recognized cGMP’s role in a wide range of physiological processes, including cardiovascular homeostasis and neuronal function. The awarding of the 1998 Nobel Prize to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad for their discoveries in the NO-cGMP pathway renewed interest in cGMP research. This led to the 1st International Conference on cGMP in 2003, which united researchers across fields and marked a milestone in coordinating scientific efforts on cGMP signaling, particularly within the cardiovascular system. https://pmc.ncbi.nlm.nih.gov/articles/PMC1369255/

Functions

Good Overview Article https://pmc.ncbi.nlm.nih.gov/articles/PMC1369255/

https://www.jacc.org/doi/full/10.1016/j.jacc.2020.08.031 Add source to first paragraph

The wording in the paragraphs is quite dense and can be cleaned up.

Pathology

Role in Major Depression Disorder

cGMP Signaling, Phosphodiesterases and Major Depressive Disorder with https://pmc.ncbi.nlm.nih.gov/articles/PMC3263465/

Cyclic guanosine monophosphate (cGMP) plays a significant role in the regulation of neuroplasticity, which is a key area of interest in understanding the pathophysiology of major depressive disorder (MDD). Neuroplasticity encompasses the brain’s ability to reorganize its structure and function in response to environmental stimuli, experiences, or injuries. Evidence suggests that deficits in neuroplasticity may underlie MDD, with disturbances observed in both synaptic plasticity (the brain’s mechanism for strengthening or weakening synaptic connections) and structural plasticity, including reduced neurogenesis.

The cGMP signaling pathway in the brain operates as a second messenger system, amplifying neurotransmitter signals and influencing gene expression and neuronal function. Within neurons, cGMP levels are modulated by guanylate cyclase enzymes, which synthesize cGMP, and by phosphodiesterases (PDEs), which degrade cGMP. Research has shown that enhancing cGMP levels, either by stimulating guanylate cyclase or inhibiting PDEs, promotes neurogenesis and synaptic plasticity, particularly in brain regions implicated in MDD, such as the hippocampus and prefrontal cortex. Animal studies also demonstrate that chronic antidepressant treatment can elevate cGMP levels in these areas, suggesting a possible link between increased cGMP activity and antidepressant efficacy. Genetic research has further highlighted specific polymorphisms in PDE genes associated with MDD susceptibility and treatment response, making components of the cGMP pathway potential targets for novel antidepressant therapies.

Role in Cardiovascular Events

Targeting Cyclic Guanosine Monophosphate to Treat Heart Failure https://www.jacc.org/doi/full/10.1016/j.jacc.2020.08.031 I like the figure

The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-phosphodiesterase (PDE) pathway has become a target in developing treatments for heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). A deficit in cGMP levels has been associated with adverse cardiovascular outcomes, promoting factors like myocardial fibrosis, vasoconstriction, and inflammation, all of which accelerate heart failure progression. Therapeutic approaches aimed at this pathway—such as sacubitril/valsartan, a combination of neprilysin inhibition and angiotensin receptor blockade, and the soluble guanylate cyclase (sGC) stimulator vericiguat—have yielded promising outcomes in reducing cardiovascular events. Sacubitril/valsartan, for example, has shown significant benefits in lowering cardiovascular mortality and hospitalization rates among HFrEF patients, establishing its role as a disease-modifying therapy in heart failure management. Vericiguat, tested in high-risk cardiac patients, has also demonstrated a reduction in heart failure hospitalizations and cardiovascular death. Its effectiveness is thought to result from increased sensitivity of sGC to endogenous NO, offering controlled blood pressure modulation with minimal hemodynamic impact. These therapies represent substantial advancements in heart failure treatment, addressing both long-term and acute care needs across diverse patient populations.

Cyclic Guanosine Monophosphate and Risk of Incident Heart Failure and Other Cardiovascular Events https://www.ahajournals.org/doi/full/10.1161/JAHA.119.013966

The relationship between cyclic guanosine monophosphate (cGMP) levels and cardiovascular disease (CVD) outcomes reveals complex roles in disease progression and potential therapeutic targeting. Elevated plasma cGMP levels, regulated predominantly by natriuretic peptides (NP) rather than nitric oxide (NO), were found to correlate with a higher risk of incident heart failure with preserved ejection fraction (HFpEF), general heart failure (HF), atherosclerotic cardiovascular disease (ASCVD), and coronary heart disease (CHD). For heart failure outcomes, particularly HFpEF, these associations appeared largely mediated by NT-proBNP—a precursor in the NP-cGMP signaling pathway—indicating that elevated cGMP might signal compensatory cardiac stress rather than a protective effect. Conversely, the association of cGMP with ASCVD and CHD persisted independently of NT-proBNP, suggesting that other non-NP-related pathways, potentially involving phosphodiesterase activity or alternate signaling mechanisms, could influence these conditions. These findings highlight a nuanced role for cGMP across cardiovascular events, where distinct signaling mechanisms may contribute differently to vascular and myocardial remodeling in ASCVD and CHD compared to HF. Future studies are essential to unravel these mechanisms and to explore the prognostic and therapeutic potential of targeting cGMP in varied cardiovascular diseases.

Role in infectious disease agents' pathogenesis

Elevated Extracellular cGMP Produced after Exposure to Enterotoxigenic Escherichia colihttps://pmc.ncbi.nlm.nih.gov/articles/PMC8090939/

In infectious disease pathogenesis, cyclic guanosine monophosphate (cGMP) can play a critical role beyond its traditional role as an intracellular messenger. Certain pathogens, such as Enterotoxigenic Escherichia coli (ETEC), utilize cGMP elevation as part of their strategy to evade host immune defenses and establish infection. ETEC’s heat-stable toxin (ST) induces significant cGMP production within intestinal epithelial cells, and this cGMP is often secreted into the extracellular space, where it serves as a signaling molecule. Extracellular cGMP, in turn, triggers the release of interleukin-33 (IL-33), an epithelial-derived cytokine that influences immune cell responses. IL-33 release can modulate inflammation and impact the immune system’s ability to mount effective responses, dampening both innate and adaptive immunity. By interfering with immune signaling pathways in this way, cGMP and IL-33 contribute to an immunosuppressive environment that may prevent the development of long-lasting immunity against ETEC, particularly in young children who are highly susceptible to infection. Thus, cGMP acts as a mediator of immune modulation, facilitating the persistence and severity of certain infections and underscoring its importance in the pathogenesis of ETEC and potentially other enteric pathogens.

Protein kinase activation

The cGMP-dependent protein kinase (PKG) activation pathway is a primary signaling mechanism through which cyclic guanosine monophosphate (cGMP) exerts its effects within cells. This pathway begins with the production of cGMP by guanylyl cyclase enzymes, which can be activated by signaling molecules such as nitric oxide (NO) or natriuretic peptides. Elevated cGMP levels then lead to the activation of PKG, a serine/threonine kinase that plays a critical role in cellular signaling.

(Back to wiki paragraph)

Once activated, PKG phosphorylates various target proteins, altering their function and contributing to cellular processes such as smooth muscle relaxation, ion channel regulation, and inhibition of platelet aggregation. In smooth muscle cells, PKG-mediated phosphorylation of myosin light chain phosphatase and calcium-activated potassium channels leads to muscle relaxation and vasodilation, which increases blood flow. Additionally, PKG influences calcium homeostasis by modulating channels and pumps that control calcium influx and efflux in the cell, thus regulating cellular contractility and other calcium-dependent processes.

This pathway is significant in cardiovascular physiology, where it helps maintain vascular tone and blood pressure. Dysregulation of the PKG pathway is associated with various pathologies, including hypertension and heart failure, making it a target for therapeutic interventions that aim to modulate cGMP or PKG activity for cardiovascular benefit. https://www.jacc.org/doi/full/10.1016/j.jacc.2020.08.031nlm.nih.gov/articles/PMC1369255/