 | |
 | |
| Names | |
|---|---|
| IUPAC name Guanosine 3′,5′-(hydrogen phosphate) | |
| Systematic IUPAC name 2-Amino-9-[(4aR,6R,7R,7aS)-2,7-dihydroxy-2-oxotetrahydro-2H,4H-2λ5-furo[3,2-d][1,3,2]dioxaphosphol-6-yl]-3,9-dihydro-6H-purin-6-one | |
| Other names cGMP; 3′,5′-cyclic GMP; 3′:5′-cyclic GMP; Guanosine cyclic monophosphate; Cyclic 3′,5′-GMP; Guanosine 3′,5′-cyclic phosphate | |
| Identifiers | |
3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
|
| ECHA InfoCard | 100.028.765 |
| MeSH | Cyclic+GMP |
| UNII | |
| |
| |
| Properties | |
| C10H12N5O7P | |
| Molar mass | 345.208 g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Cyclic guanosine monophosphate (cGMP) is acyclic nucleotide derived fromguanosine triphosphate (GTP). cGMP acts as asecond messenger much likecyclic AMP. Its most likely mechanism of action is activation of intracellularprotein kinases in response to the binding ofmembrane-impermeablepeptide hormones to the external cell surface.[1] Through protein kinases activation, cGMP can relax smooth muscle.[2] cGMP concentration in urine can be measured for kidney function and diabetes detection.[3]
Cyclic guanosine monophosphate (cGMP) research began after cGMP andcyclic adenosine monophosphate (cAMP) were identified as cellular components and potentially involved with cellular regulation.[4] Upon the synthesis of cGMP in 1960,[4] progress rapidly spread in the understanding of regulation and effects of cGMP.Earl W. Sutherland received the 1971Nobel Prize in Medicine for his work withcAMP andsecondary messengers. This award sparked extensive research intocAMP, while cGMP received less attention, with its biological functions largely unknown until the 1980s.[5] 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 particulateguanylyl cyclase (pGC) receptor, andnitric oxide (NO), identified as the endothelium-derived relaxing factor, was shown to activatesoluble guanylyl cyclase (sGC), producing cGMP to mediatevasodilation in smooth muscle cells.[5] Further components involved with the cGMP were also identified such as cGMP-hydrolyzingphosphodiesterases (PDEs) and cGMP-binding proteins.[5] The awarding of the 1998Nobel Prize toRobert F. Furchgott,Louis J. Ignarro, andFerid Murad for their discoveries in the NO-cGMP pathway renewed interest in cGMP research with the 1st International Conference on cGMP being held in 2003.[5]
Guanylate cyclase (GC)catalyzes cGMP synthesis. This enzyme convertsGTP to cGMP. Peptide hormones such as theatrial natriuretic factor activate membrane-bound GC, while soluble GC (sGC) is typically activated bynitric oxide to stimulate cGMP synthesis. sGC can be inhibited by ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one).[6]
cGMP acts as a regulator of ion channel conductance, glycogenolysis, cellular apoptosis, and platelet inhibition. cGMP relaxes smooth muscle tissue leading to vasodilation which increases blood flow. Additionally, cGMP is involved with neurogenesis andneuroplasticity. At presynaptic terminals in thestriatum, cGMP controls the efficacy ofneurotransmitter release.[7]
cGMP is a secondary messenger inphototransduction in the eye. In the photoreceptors of the mammalian eye, the presence of light activatesphosphodiesterase, which degrades cGMP. Thesodium ion channels in photoreceptors are cGMP-gated, so degradation of cGMP causes sodium channels to close, which leads to the hyperpolarization of the photoreceptor's plasma membrane and ultimately to visual information being sent to the brain.[8]
cGMP is also seen to mediate the switching on of the attraction ofapical dendrites ofpyramidal cells incortical layer V towardssemaphorin-3A (Sema3a).[9] Whereas theaxons of pyramidal cells are repelled by Sema3a, the apical dendrites are attracted to it. The attraction is mediated by the increased levels ofsoluble guanylate cyclase (sGC) that are present in the apical dendrites. sGC generates cGMP, leading to a sequence of chemical activations that result in the attraction towards Sema3a. The absence of sGC in the axon causes the repulsion from Sema3a. This strategy ensures the structural polarization of pyramidal neurons and takes place in embryonic development.
cGMP, like cAMP, gets synthesized when olfactory receptors receive odorous input. cGMP is produced slowly and has a more sustained life than cAMP, which has implicated it in long-term cellular responses to odor stimulation, such aslong-term potentiation. cGMP in the olfactory is synthesized by both membrane guanylyl cyclase (mGC) as well as soluble guanylyl cyclase (sGC). Studies have found that cGMP synthesis in the olfactory is due to sGC activation by nitric oxide, a neurotransmitter. cGMP also requires increased intracellular levels of cAMP and the link between the twosecond messengers appears to be due to rising intracellular calcium levels.[10]
Thenitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-phosphodiesterase (PDE) pathway has become a target in developing treatments for heart failure. A deficit in cGMP levels has been associated with adversecardiovascular outcomes, promoting factors likemyocardial fibrosis,vasoconstriction, andinflammation, all of which accelerateheart failure progression.[11] Some solubleguanylate cyclase (sGC) stimulators, have yielded promising outcomes in reducing cardiovascular events.[11] Their effectiveness is thought to result from increased sensitivity of sGC to endogenous NO.
Elevated plasma cGMP levels, regulated predominantly bynatriuretic peptides (NP) rather thannitric oxide (NO), were found to correlate with a higher risk of heart failure, atherosclerotic cardiovascular disease, andcoronary heart disease.[12]
The cGMP signaling pathway plays a role in the regulation ofneuroplasticity, an area of interest in understanding the pathophysiology ofmajor depressive disorder (MDD).[13] The cGMP signaling pathway in the brain operates as asecond messenger system, amplifyingneurotransmitter signals, influencinggene expression and neuronal function. Within neurons, cGMP levels are modulated by guanylate cyclaseenzymes, which synthesize cGMP, and by PDEs, which degrade cGMP.[13]
Enhancing cGMP levels, either by stimulating guanylate cyclase or inhibiting PDEs, promotesneurogenesis and synapticplasticity, particularly in brain regions implicated inMDD, such as thehippocampus andprefrontal cortex.[13] Animal studies also demonstrate that chronicantidepressant treatment can elevate cGMP levels in these areas.[13] Genetic research has further highlighted specific polymorphisms in PDE genes associated with MDD susceptibility and treatment response.[13]
Certain pathogens, such asEnterotoxigenic Escherichia coli (ETEC), elevate cGMP to evade host immune defenses and establish infection. ETEC's heat-stable toxin 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.[14] Extracellular cGMP, in turn, triggers the release of IL-33 release which modulate inflammation and impact the immune system's ability to mount effective responses, dampening both innate and adaptive immunity.[14][15]
Numerous cyclic nucleotidephosphodiesterases (PDE) can degrade cGMP byhydrolyzing cGMP into 5'-GMP. PDE 5, -6 and -9 are cGMP-specific while PDE1, -2, -3, -10 and -11 can hydrolyse both cAMP and cGMP.
Phosphodiesterase inhibitors prevent the degradation of cGMP, thereby enhancing and/or prolonging its effects. For example,Sildenafil (Viagra) and similar drugs enhance the vasodilatory effects of cGMP within thecorpus cavernosum by inhibiting PDE 5 (or PDE V). This is used as a treatment forerectile dysfunction. However, the drug can inhibit PDE6 in retina (albeit with less affinity than PDE5). This has been shown to result in loss of visual sensitivity but is unlikely to impair common visual tasks, except under conditions of reduced visibility when objects are already near visual threshold.[16] This effect is largely avoided by other PDE5 inhibitors, such astadalafil.[17]
The cGMP-dependent protein kinase (PKG) activation pathway begins with the production of cGMP byguanylyl cyclase enzymes, which can be activated by signaling molecules such asnitric oxide (NO) ornatriuretic peptides. Elevated cGMP levels then lead to the activation of some protein-dependent kinases like PKG.[5] For example, PKG (protein kinase G) is adimer consisting of onecatalytic and one regulatory unit, with the regulatory units blocking theactive sites of the catalytic units.
cGMP binds to sites on the regulatory units of PKG and activates the catalytic units, enabling them to phosphorylate their substrates. Unlike with the activation of some other protein kinases, notably PKA, the PKG is activated but the catalytic and regulatory units do not disassociate.
Once activated, PKGphosphorylates various target proteins, altering their function and contributing to cellular processes such as smooth muscle relaxation, ion channel regulation, and inhibition of platelet aggregation. This pathway is also significant in cardiovascular physiology, where it helps maintain vascular tone andblood pressure.[11]
