Cyclic guanosine monophosphate

Last updated
Cyclic guanosine monophosphate
CGMP2.svg
Cyclic-guanosine-monophosphate-anion-3D-spacefill.png
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 OOjs UI icon edit-ltr-progressive.svg
MeSH Cyclic+GMP
PubChem CID
UNII
  • InChI=1S/C10H12N5O7P/c11-10-13-7-4(8(17)14-10)12-2-15(7)9-5(16)6-3(21-9)1-20-23(18,19)22-6/h2-3,5-6,9,16H,1H2,(H,18,19)(H3,11,13,14,17)/t3-,5-,6-,9-/m1/s1 Yes check.svgY
    Key: ZOOGRGPOEVQQDX-UUOKFMHZSA-N Yes check.svgY
  • InChI=1/C10H12N5O7P/c11-10-13-7-4(8(17)14-10)12-2-15(7)9-5(16)6-3(21-9)1-20-23(18,19)22-6/h2-3,5-6,9,16H,1H2,(H,18,19)(H3,11,13,14,17)/t3-,5-,6-,9-/m1/s1
    Key: ZOOGRGPOEVQQDX-UUOKFMHZBB
  • O=C4/N=C(/N)Nc1c4ncn1[C@@H]2O[C@@H]3COP(=O)(O[C@H]3[C@H]2O)O
Properties
C10H12N5O7P
Molar mass 345.208 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in response to the binding of membrane-impermeable peptide 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]

Contents

History

Cyclic guanosine monophosphate (cGMP) research began after cGMP and cyclic 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 1971 Nobel Prize in Medicine for his work with cAMP and secondary messengers. This award sparked extensive research into cAMP, 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 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 vasodilation in smooth muscle cells. [5] Further components involved with the cGMP were also identified such as cGMP-hydrolyzing phosphodiesterases (PDEs) and cGMP-binding proteins. [5] 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 with the 1st International Conference on cGMP being held in 2003. [5]

Synthesis

Guanylate cyclase (GC) catalyzes cGMP synthesis. This enzyme converts GTP to cGMP. Peptide hormones such as the atrial natriuretic factor activate membrane-bound GC, while soluble GC (sGC) is typically activated by nitric oxide to stimulate cGMP synthesis. sGC can be inhibited by ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). [6]

Ball and Stick model of the cyclic guanosine monophosphate molecule, Color code: Carbon, C: black Hydrogen, H: white Oxygen, O: red Nitrogen, N: blue Phosphorus, P: orange. Cyclic-guanosine-monophosphate-anion-ball-and-stick.png
Ball and Stick model of the cyclic guanosine monophosphate molecule, Color code: Carbon, C: black Hydrogen, H: white Oxygen, O: red Nitrogen, N: blue   Phosphorus, P: orange.

Functions

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 and neuroplasticity. At presynaptic terminals in the striatum, cGMP controls the efficacy of neurotransmitter release. [7]

cGMP is a secondary messenger in phototransduction in the eye. In the photoreceptors of the mammalian eye, the presence of light activates phosphodiesterase, which degrades cGMP. The sodium 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 of apical dendrites of pyramidal cells in cortical layer V towards semaphorin-3A (Sema3a). [9] Whereas the axons of pyramidal cells are repelled by Sema3a, the apical dendrites are attracted to it. The attraction is mediated by the increased levels of soluble 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 as long-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 two second messengers appears to be due to rising intracellular calcium levels. [10]

Schematic of cGMP and a broad overview of its effects Schematic of cGMP.jpg
Schematic of cGMP and a broad overview of its effects

Pathology

Role in Cardiovascular Events

The nitric 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 adverse cardiovascular outcomes, promoting factors like myocardial fibrosis, vasoconstriction, and inflammation, all of which accelerate heart failure progression. [11] Some soluble guanylate 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 by natriuretic peptides (NP) rather than nitric oxide (NO), were found to correlate with a higher risk of heart failure, atherosclerotic cardiovascular disease, and coronary heart disease. [12]

Role in Major Depression Disorder

The cGMP signaling pathway plays a role in the regulation of neuroplasticity, an area of interest in understanding the pathophysiology of major depressive disorder (MDD). [13] The cGMP signaling pathway in the brain operates as a second messenger system, amplifying neurotransmitter signals, influencing gene expression and neuronal function. Within neurons, cGMP levels are modulated by guanylate cyclase enzymes, which synthesize cGMP, and by PDEs, which degrade cGMP. [13]

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. [13] Animal studies also demonstrate that chronic antidepressant 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]

Role in Infectious Disease Pathogenesis

Certain pathogens, such as Enterotoxigenic 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]

Degradation

Numerous cyclic nucleotide phosphodiesterases (PDE) can degrade cGMP by hydrolyzing 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 the corpus cavernosum by inhibiting PDE 5 (or PDE V). This is used as a treatment for erectile 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 as tadalafil. [17]

role of PKG in cellular system CGMP-Rezeptoren.jpg
role of PKG in cellular system

Protein kinase activation

The cGMP-dependent protein kinase (PKG) activation 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 some protein-dependent kinases like PKG. [5] For example, PKG (protein kinase G) is a dimer consisting of one catalytic and one regulatory unit, with the regulatory units blocking the active 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, 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. This pathway is also significant in cardiovascular physiology, where it helps maintain vascular tone and blood pressure. [11]

See also

Related Research Articles

<span class="mw-page-title-main">Cyclic adenosine monophosphate</span> Cellular second messenger

Cyclic adenosine monophosphate is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.

<span class="mw-page-title-main">Cyclic nucleotide</span> Cyclic nucleic acid

A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.

<span class="mw-page-title-main">Phosphodiesterase</span> Class of enzymes

A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.

<span class="mw-page-title-main">Transducin</span>

Transducin (Gt) is a protein naturally expressed in vertebrate retina rods and cones and it is very important in vertebrate phototransduction. It is a type of heterotrimeric G-protein with different α subunits in rod and cone photoreceptors.

<span class="mw-page-title-main">Guanylate cyclase</span> Lyase enzyme that synthesizes cGMP from GTP

Guanylate cyclase is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) and pyrophosphate:

<span class="mw-page-title-main">Guanosine monophosphate</span> Chemical compound

Guanosine monophosphate (GMP), also known as 5′-guanidylic acid or guanylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside guanosine. GMP consists of the phosphate group, the pentose sugar ribose, and the nucleobase guanine; hence it is a ribonucleotide monophosphate. Guanosine monophosphate is commercially produced by microbial fermentation.

cGMP-specific phosphodiesterase type 5 Mammalian protein found in humans

Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum of the clitoris and of the penis as well as the retina. It has also been recently discovered to play a vital role in the cardiovascular system.

<span class="mw-page-title-main">Nicorandil</span> Chemical compound

Nicorandil is a vasodilator drug used to treat angina.

<span class="mw-page-title-main">Cyclic nucleotide phosphodiesterase</span> Class of enzymes

3′,5′-cyclic-nucleotide phosphodiesterases (EC 3.1.4.17) are a family of phosphodiesterases. Generally, these enzymes hydrolyze a nucleoside 3′,5′-cyclic phosphate to a nucleoside 5′-phosphate:

Phosphodiesterase 1, PDE1, EC 3.1.4.1, systematic name oligonucleotide 5′-nucleotidohydrolase) is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). Phosphodiesterase 1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. The various isoforms exhibit different affinities for cAMP and cGMP.

An atrial natriuretic peptide receptor is a receptor for atrial natriuretic peptide.

<span class="mw-page-title-main">Soluble guanylyl cyclase</span>

Soluble guanylyl cyclase (sGC) is one of the gasoreceptors for nitric oxide, NO. It is soluble, i.e. completely intracellular. Most notably, this enzyme is involved in vasodilation. In humans, it is encoded by the genes GUCY1A2, GUCY1A3, GUCY1B2 and GUCY1B3.

<span class="mw-page-title-main">GUCY1B3</span> Protein-coding gene in the species Homo sapiens

Guanylate cyclase soluble subunit beta-1 is an enzyme that in humans is encoded by the GUCY1B3 gene.

<span class="mw-page-title-main">Nitrovasodilator</span> Drug that causes vasodilation by releasing nitric oxide

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<span class="mw-page-title-main">Riociguat</span> Chemical compound

Riociguat, sold under the brand name Adempas, is a medication by Bayer that is a stimulator of soluble guanylate cyclase (sGC). It is used to treat two forms of pulmonary hypertension (PH): chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat constitutes the first drug of the class of sGC stimulators. The drug has a half-life of 12 hours and will decrease dyspnea associated with pulmonary arterial hypertension.

<span class="mw-page-title-main">Diguanylate cyclase</span>

In enzymology, diguanylate cyclase, also known as diguanylate kinase, is an enzyme that catalyzes the chemical reaction:

Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.

<span class="mw-page-title-main">Cyclic di-AMP</span> Chemical compound

Cyclic di-AMP is a second messenger used in signal transduction in bacteria and archaea. It is present in many Gram-positive bacteria, some Gram-negative species, and archaea of the phylum Euryarchaeota.

Hydrogen sulfide is produced in small amounts by some cells of the mammalian body and has a number of biological signaling functions. Only two other such gases are currently known: nitric oxide (NO) and carbon monoxide (CO).

Resumption of meiosis occurs as a part of oocyte meiosis after meiotic arrest has occurred. In females, meiosis of an oocyte begins during embryogenesis and will be completed after puberty. A primordial follicle will arrest, allowing the follicle to grow in size and mature. Resumption of meiosis will resume following an ovulatory surge (ovulation) of luteinising hormone (LH).

References

  1. ↑ Francis SH, Corbin JD (August 1999). "Cyclic nucleotide-dependent protein kinases: intracellular receptors for cAMP and cGMP action". Critical Reviews in Clinical Laboratory Sciences. 36 (4): 275–328. doi:10.1080/10408369991239213. PMID   10486703.
  2. ↑ Carvajal JA, Germain AM, Huidobro-Toro JP, Weiner CP (September 2000). "Molecular mechanism of cGMP-mediated smooth muscle relaxation". Journal of Cellular Physiology. 184 (3): 409–420. doi: 10.1002/1097-4652(200009)184:3<409::aid-jcp16>3.0.co;2-k . PMID   10911373. S2CID   22530053.
  3. ↑ Chaykovska L, Heunisch F, von Einem G, Hocher CF, Tsuprykov O, Pavkovic M, et al. (2018-04-12). Shimosawa T (ed.). "Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium". PLOS ONE. 13 (4): e0195828. Bibcode:2018PLoSO..1395828C. doi: 10.1371/journal.pone.0195828 . PMC   5896998 . PMID   29649334.
  4. 1 2 Kots, Alexander Y.; Martin, Emil; Sharina, Iraida G.; Murad, Ferid (2009), Schmidt, Harald H. H. W.; Hofmann, Franz; Stasch, Johannes-Peter (eds.), "A Short History of cGMP, Guanylyl Cyclases, and cGMP-Dependent Protein Kinases", cGMP: Generators, Effectors and Therapeutic Implications, vol. 191, Berlin, Heidelberg: Springer Berlin Heidelberg, pp. 1–14, doi:10.1007/978-3-540-68964-5_1, ISBN   978-3-540-68960-7, PMID   19089322 , retrieved 2024-11-27
  5. 1 2 3 4 5 Feil, Robert; Kemp-Harper, Barbara (Feb 2006). "cGMP signalling: from bench to bedside: Conference on cGMP Generators, Effectors and Therapeutic Implications". EMBO Reports. 7 (2): 149–153. doi:10.1038/sj.embor.7400627. ISSN   1469-221X. PMC   1369255 . PMID   16439998.
  6. ↑ Garthwaite J, Southam E, Boulton CL, Nielsen EB, Schmidt K, Mayer B (August 1995). "Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one". Molecular Pharmacology. 48 (2): 184–188. PMID   7544433.
  7. ↑ Fieblinger T, Perez-Alvarez A, Lamothe-Molina PJ, Gee CE, Oertner TG (August 2022). "Presynaptic cGMP sets synaptic strength in the striatum and is important for motor learning". EMBO Reports. 23 (8): e54361. doi:10.15252/embr.202154361. PMC   9346481 . PMID   35735260.
  8. ↑ Brown RL, Strassmaier T, Brady JD, Karpen JW (2006). "The pharmacology of cyclic nucleotide-gated channels: emerging from the darkness". Current Pharmaceutical Design. 12 (28): 3597–3613. doi:10.2174/138161206778522100. PMC   2467446 . PMID   17073662. NIHMSID: NIHMS47625.
  9. ↑ Polleux F, Morrow T, Ghosh A (April 2000). "Semaphorin 3A is a chemoattractant for cortical apical dendrites". Nature. 404 (6778): 567–573. Bibcode:2000Natur.404..567P. doi:10.1038/35007001. PMID   10766232. S2CID   4365085.
  10. ↑ Pietrobon M, Zamparo I, Maritan M, Franchi SA, Pozzan T, Lodovichi C (June 2011). "Interplay among cGMP, cAMP, and Ca2+ in living olfactory sensory neurons in vitro and in vivo". The Journal of Neuroscience. 31 (23): 8395–8405. doi: 10.1523/JNEUROSCI.6722-10.2011 . PMC   6623327 . PMID   21653844.
  11. 1 2 3 Emdin, Michele; Aimo, Alberto; Castiglione, Vincenzo; Vergaro, Giuseppe; Georgiopoulos, Georgios; Saccaro, Luigi Francesco; Lombardi, Carlo Mario; Passino, Claudio; Cerbai, Elisabetta; Metra, Marco; Senni, Michele (2020-10-13). "Targeting Cyclic Guanosine Monophosphate to Treat Heart Failure: JACC Review Topic of the Week". Journal of the American College of Cardiology. 76 (15): 1795–1807. doi:10.1016/j.jacc.2020.08.031. ISSN   0735-1097 – via Elsevier Science Direct.
  12. ↑ Zhao, Di; Guallar, Eliseo; Vaidya, Dhananjay; Ndumele, Chiadi E.; Ouyang, Pamela; Post, Wendy S.; Lima, Joao A.; Ying, Wendy; Kass, David A.; Hoogeveen, Ron C.; Shah, Sanjiv J.; Subramanya, Vinita; Michos, Erin D. (2020-01-21). "Cyclic Guanosine Monophosphate and Risk of Incident Heart Failure and Other Cardiovascular Events: the ARIC Study". Journal of the American Heart Association. 9 (2): e013966. doi:10.1161/JAHA.119.013966. ISSN   2047-9980. PMC   7033823 . PMID   31928156.
  13. 1 2 3 4 5 W. Reierson, Gillian; Guo, Shuyu; Mastronardi, Claudio; Licinio, Julio; Wong, Ma-Li (2011-12-01). "cGMP Signaling, Phosphodiesterases and Major Depressive Disorder". Current Neuropharmacology. 9 (4): 715–727. doi:10.2174/157015911798376271. PMC   3263465 . PMID   22654729.
  14. 1 2 Motyka, Natalya I.; Stewart, Sydney R.; Hollifield, Ian E.; Kyllo, Thomas R.; Mansfield, Joshua A.; Norton, Elizabeth B.; Clements, John D.; Bitoun, Jacob P. (2021-03-17). Torres, Victor J. (ed.). "Elevated Extracellular cGMP Produced after Exposure to Enterotoxigenic Escherichia coli Heat-Stable Toxin Induces Epithelial IL-33 Release and Alters Intestinal Immunity". Infection and Immunity. 89 (4). doi:10.1128/IAI.00707-20. ISSN   0019-9567. PMC   8090939 . PMID   33431701.
  15. ↑ Wang, Haixiu; Zhong, Zifu; Luo, Yu; Cox, Eric; Devriendt, Bert (2019-01-08). "Heat-Stable Enterotoxins of Enterotoxigenic Escherichia coli and Their Impact on Host Immunity". Toxins. 11 (1): 24. doi: 10.3390/toxins11010024 . hdl: 1854/LU-8588551 . ISSN   2072-6651. PMID   30626031.
  16. ↑ Stockman A, Sharpe LT, Tufail A, Kell PD, Ripamonti C, Jeffery G (June 2007). "The effect of sildenafil citrate (Viagra) on visual sensitivity". Journal of Vision. 7 (8): 4. doi: 10.1167/7.8.4 . PMID   17685811.
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