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; 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

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). [4]

Functions

cGMP is a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. It also relaxes smooth muscle tissues. In blood vessels, relaxation of vascular smooth muscles leads to vasodilation and increased blood flow. At presynaptic terminals in the striatum, cGMP controls the efficacy of neurotransmitter release. [5]

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. [6]

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). [7] 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. [8]

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. [9] This effect is largely avoided by other PDE5 inhibitors, such as tadalafil. [10]

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

Protein kinase activation

cGMP is involved in the regulation of some protein-dependent kinases. 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.

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">Phosphodiesterase inhibitor</span> Drug

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

<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">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

<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">Rod cell</span> Photoreceptor cells that can function in lower light better than cone cells

Rod cells are photoreceptor cells in the retina of the eye that can function in lower light better than the other type of visual photoreceptor, cone cells. Rods are usually found concentrated at the outer edges of the retina and are used in peripheral vision. On average, there are approximately 92 million rod cells in the human retina. Rod cells are more sensitive than cone cells and are almost entirely responsible for night vision. However, rods have little role in color vision, which is the main reason why colors are much less apparent in dim light.

<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:

cGMP-specific phosphodiesterase type 5 Mammalian protein found in Homo sapiens

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 and the retina. It has also been recently discovered to play a vital role in the cardiovascular system.

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

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

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:

<span class="mw-page-title-main">Phosphodiesterase 3</span> Class of enzymes

PDE3 is a phosphodiesterase. The PDEs belong to at least eleven related gene families, which are different in their primary structure, substrate affinity, responses to effectors, and regulation mechanism. Most of the PDE families are composed of more than one gene. PDE3 is clinically significant because of its role in regulating heart muscle, vascular smooth muscle and platelet aggregation. PDE3 inhibitors have been developed as pharmaceuticals, but their use is limited by arrhythmic effects and they can increase mortality in some applications.

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.

<span class="mw-page-title-main">Phosphodiesterase 2</span> Class of enzymes

The PDE2 enzyme is one of 21 different phosphodiesterases (PDE) found in mammals. These different PDEs can be subdivided to 11 families. The different PDEs of the same family are functionally related despite the fact that their amino acid sequences show considerable divergence. The PDEs have different substrate specificities. Some are cAMP selective hydrolases, others are cGMP selective hydrolases and the rest can hydrolyse both cAMP and cGMP.

<span class="mw-page-title-main">PDE11A</span> Protein-coding gene in the species Homo sapiens

Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A is an enzyme that in humans is encoded by the PDE11A gene.

<span class="mw-page-title-main">PDE10A</span> Enzyme and protein-coding gene in humans

cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A is an enzyme that in humans is encoded by the PDE10A gene.

In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.

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.

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. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H, Linget JM, et al. (October 2003). "The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues". Journal of Medicinal Chemistry. 46 (21): 4533–4542. doi:10.1021/jm0300577. PMID   14521415.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.