Cyclic nucleotide

Last updated
Cyclic adenosine monophosphate. The cyclic portion refers to the two single bonds between the phosphate group and the ribose Cyclic-adenosine-monophosphate-2D-skeletal.png
Cyclic adenosine monophosphate. The cyclic portion refers to the two single bonds between the phosphate group and the ribose

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.

Contents

Their biological significance includes a broad range of protein-ligand interactions. They have been identified as secondary messengers in both hormone and ion-channel signalling in eukaryotic cells, as well as allosteric effector compounds of DNA binding proteins in prokaryotic cells. cAMP and cGMP are currently the most well documented cyclic nucleotides, however there is evidence that cCMP (with cytosine) is also involved in eukaryotic cellular messaging. The role of cyclic uridine monophosphate (cUMP) is even less well known.

Discovery of cyclic nucleotides has contributed greatly to the understanding of kinase and phosphatase mechanisms, as well as protein regulation in general. Although more than 50 years have passed since their initial discovery, interest in cyclic nucleotides and their biochemical and physiological significance continues.

History

The understanding of the concept of second messengers, and in particular the role of cyclic nucleotides and their ability to relay physiological signals to a cell, has its origins in the research of glycogen metabolism by Carl and Gerty Cori, for which they were awarded a Nobel Prize in Physiology or Medicine in 1947. [1] A number of incremental but important discoveries through the 1950s added to their research, primarily focusing on the activity of glycogen phosphorylase in dog liver. Glycogen phosphorylase catalyzes the first step in glycogenolysis, the process of breaking glycogen into its substituent glucose parts. [2] Earl Sutherland investigated the effect of the hormones adrenaline and glucagon on glycogen phosphorylase, earning him the Nobel Prize in Physiology or Medicine in 1971. [1]

In 1956 Edwin Krebs and Edmond Fischer discovered that adenosine triphosphate (ATP) is required for the conversion of glycogen phosphorylase b to glycogen phosphorylase a. While investigating the action of adrenaline on glycogenolysis the next year, Sutherland and Walter Wosilait reported that inorganic phosphate is released when the enzyme liver phosphorylase is inactivated; but when it is activated, it incorporates a phosphate. [1] The “active factor” that the hormones produced [2] was finally purified in 1958, and then identified as containing a ribose, a phosphate, and an adenine in equal ratios. Further, it was proved that this factor reverted to 5’-AMP when it was inactivated. [1]

Evgeny Fesenko, Stanislav Kolesnikov, and Arkady Lyubarsky discovered in 1985 that cyclic guanosine monophosphate (cGMP) can initiate the photoresponse in rods. Soon after, the role of cNMP in gated ion channels of chemosensitive cilia of olfactory sensory neurons was reported by Tadashi Nakamura and Geoffrey Gold. In 1992 Lawrence Haynes and King-Wai Yau uncovered cNMP’s role in the light-dependent cyclic-nucleotide-gated channel of cone photoreceptors. [3] By the end of the decade, the presence of two types of intramembrane receptors was understood: Rs (which stimulates cyclase) and Ri (which inhibits cyclase). Wei-Jen Tang and James Hurley reported in 1998 that adenylyl cyclase, which synthesizes cAMP, is regulated not only by hormones and neurotransmitters, but also by phosphorylation, calcium, forskolin, and guanine nucleotide-binding proteins (G proteins). [2]

Chemistry of cNMPs

Structure

Cyclic guanosine monophosphate. The cyclic portion refers to the two single bonds between the phosphate group and the ribose CGMP.png
Cyclic guanosine monophosphate. The cyclic portion refers to the two single bonds between the phosphate group and the ribose

The two most well-studied cyclic nucleotides are cyclic AMP (cAMP) and cyclic GMP (cGMP), while cyclic CMP (cCMP) and cyclic UMP (cUMP) are less understood. cAMP is 3’5’-cyclic adenosine monophosphate, cGMP is 3’5’-cyclic guanosine monophosphate, cCMP is cytidine 3',5'-monophosphate, and cUMP is uridine 3',5'-cyclic phosphate. [4] [5]

Each cyclic nucleotide has three components. It contains a nitrogenous base (meaning it contains nitrogen): for example, adenine in cAMP and guanine in cGMP. It also contains a sugar, specifically the five-carbon ribose. And finally, a cyclic nucleotide contains a phosphate. A double-ring purine is the nitrogenous base for cAMP and cGMP, while cytosine, thymine, and uracil each have a single-ring nitrogenous base (pyrimidine).

These three components are connected so that the nitrogenous base is attached to the first carbon of ribose (1’ carbon), and the phosphate group is attached to the 5’ carbon of ribose. While all nucleotides have this structure, the phosphate group makes a second connection to the ribose ring at the 3’ carbon in cyclic nucleotides. Because the phosphate group has two separate bonds to the ribose sugar, it forms a cyclic ring. [6]

The atom numbering convention is used to identify the carbons and nitrogens within a cyclic nucleotide. In the pentose, the carbon closest to the carbonyl group is labeled C-1. When a pentose is connected to a nitrogenous base, carbon atom numbering is distinguished with a prime (') notation, which differentiates these carbons from the atom numbering of the nitrogenous base. [7]

Therefore, for cAMP, 3’5’-cyclic adenosine monophosphate indicates that a single phosphate group forms a cyclic structure with the ribose group at its 3’ and 5’ carbons, while the ribose group is also attached to adenosine (this bond is understood to be at the 1’ position of the ribose).

Biochemistry

Cyclic nucleotides are found in both prokaryotic and eukaryotic cells. Control of intracellular concentrations is maintained through a series of enzymatic reactions involving several families of proteins. In higher order mammals, cNMPs are present in many types of tissue.

Synthesis and Degradation

Generic cyclic nucleotide biosynthesis reaction by cyclase Cyclic nucleotide synthesis.png
Generic cyclic nucleotide biosynthesis reaction by cyclase

Cyclic nucleotides are produced from the generic reaction NTP → cNMP + PPi, [8] where N represents a nitrogenous base. The reaction is catalyzed by specific nucleotidyl cyclases, such that production of cAMP is catalyzed by adenylyl cyclase and production of cGMP is catalyzed by guanylyl cyclase. [2] Adenylyl cyclase has been found in both a transmembrane and cytosolic form, representing distinct protein classes and different sources of cAMP. [9]

Generic hydrolysis reaction of 3' cNMP phosphodiester bond by phosphodiesterase Hydrolisis of 3' cNMP phosphodiester bond by phosphodiesterase.png
Generic hydrolysis reaction of 3' cNMP phosphodiester bond by phosphodiesterase

Both cAMP and cGMP are degraded by hydrolysis of the 3' phosphodiester bond, resulting in a 5'NMP. Degradation is carried out primarily by a class of enzymes known as phosphodiesterases (PDEs). In mammalian cells, there are 11 known PDE families with varying isoforms of each protein expressed based on the cell's regulatory needs. Some phosphodiesterases are cNMP-specific, while others can hydrolyze non-specifically. [10] However, the cAMP and cGMP degradation pathways are much more understood than those for either cCMP or cUMP. The identification of specific PDEs for cCMP and cUMP has not been as thoroughly established. [11]

Target Binding

Cyclic nucleotides can be found in many different types of eukaryotic cells, including photo-receptor rods and cones, smooth muscle cells and liver cells. Cellular concentrations of cyclic nucleotides can be very low, in the 10−7 M range, because metabolism and function are often localized in particular parts of the cell. [1] A highly conserved cyclic nucleotide-binding domain (CNB) is present in all proteins that bind cNMPs, regardless of their biological function. The domain consists of a beta sandwich architecture, with the cyclic nucleotide binding pocket between the beta sheets. The binding of cNMP causes a conformational change that affects the protein's activity. [12] There is also data to support a synergistic binding effect amongst multiple cyclic nucleotides, with cCMP lowering the effective concentration (EC50) of cAMP for activation of protein kinase A (PKA). [13]

Biology

Cyclic nucleotides are integral to a communication system that acts within cells. [1] They act as "second messengers" by relaying the signals of many first messengers, such as hormones and neurotransmitters, to their physiological destinations. Cyclic nucleotides participate in many physiological responses, [14] including receptor-effector coupling, down-regulation of drug responsiveness, protein-kinase cascades, and transmembrane signal transduction. [1]

Cyclic nucleotides act as second messengers when first messengers, which cannot enter the cell, instead bind to receptors in the cellular membrane. The receptor changes conformation and transmits a signal that activates an enzyme in the cell membrane interior called adenylyl cyclase. This releases cAMP into the cell interior, where it stimulates a protein kinase called cyclic AMP-dependent protein kinase. By phosphorylating proteins, cyclic AMP-dependent protein kinase alters protein activity. cAMP's role in this process terminates upon hydrolysis to AMP by phosphodiesterase. [2]

Cyclic nucleotideKnown binding proteinsPathway/Biological association
cAMP
  1. protein kinase A
  2. cyclic nucleotide-gated ion channels
  3. Epac
  4. Catabolite Activator Protein (CAP)
  1. smooth muscle relaxation [15]
  2. photo/olfactory receptors [3]
  3. glucagon production in pancreatic beta cells [16]
  4. lac operon regulation in E. coli [17] [18]
cGMP
  1. cGMP-dependent protein kinase (PKG)
  2. cyclic nucleotide-gated ion channels
  1. smooth muscle relaxation [15]
  2. photo/olfactory receptors [3]
cCMP
  1. cGMP kinase I
  2. protein kinase A
  1. smooth muscle relaxation [13] [19]

Cyclic nucleotides are well-suited to act as second messengers for several reasons. Their synthesis is energetically favorable, and they are derived from common metabolic components (ATP and GTP). When they break down into AMP/GMP and inorganic phosphate, these components are non-toxic. [14] Finally, cyclic nucleotides can be distinguished from non-cyclic nucleotides because they are smaller and less polar. [2]

Biological significance

The involvement of cyclic nucleotides on biological functions is varied, while an understanding of their role continues to grow. There are several examples of their biological influence. They are associated with long-term and short-term memory. [20] They also work in the liver to coordinate various enzymes that control blood glucose and other nutrients. [21] In bacteria, cyclic nucleotides bind to catabolite gene activator protein (CAP), which acts to increase metabolic enzymatic activity by increasing the rate of DNA transcription. [5] They also facilitate relaxation of smooth muscle cells in vascular tissue, [22] and activate cyclic CNG channels in retinal photoreceptors and olfactory sensory neurons. In addition, they potentially activate cyclic CNG channels in: pineal gland light sensitivity, sensory neurons of the vomeronasal organ (which is involved in the detection of pheromones), taste receptor cells, cellular signaling in sperm, airway epithelial cells, gonadotropin-releasing hormone (GnRH)-secreting neuronal cell line, and renal inner medullary collecting duct. [3]

Examples of disruptions of cNMP pathways include: mutations in CNG channel genes are associated with degeneration of the retina and with color blindness; [3] and overexpression of cytosolic or soluble adenylyl cyclase (sAC) has been linked to human prostate carcinoma. Inhibition of sAC, or knockdown by RNA interference (RNAi) transfection has been shown to prevent the proliferation of the prostate carcinoma cells. The regulatory pathway appears to be part of the EPAC pathway and not the PKA pathway. [9]

Phosphodiesterases, principle regulators of cNMP degradation, are often targets for therapeutics. Caffeine is a known PDE inhibitor, while drugs used for the treatment of erectile dysfunction like sildenafil and tadalafil also act through inhibiting the activity of phosphodiesterases. [10]

Related Research Articles

<span class="mw-page-title-main">Adenylyl cyclase</span> Enzyme with key regulatory roles in most cells

Adenylate cyclase is an enzyme with systematic name ATP diphosphate-lyase . It catalyzes the following reaction:

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

Cyclic adenosine monophosphate is a second messenger 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">Nucleotide</span> Biological molecules that form the building blocks of nucleic acids

Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.

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

Adenosine monophosphate (AMP), also known as 5'-adenylic acid, is a nucleotide. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine; it is an ester of phosphoric acid and the nucleoside adenosine. As a substituent it takes the form of the prefix adenylyl-.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of enzymes 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">Cyclic guanosine monophosphate</span> Chemical compound

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.

<span class="mw-page-title-main">Ribonucleotide</span> Nucleotide containing ribose as its pentose component

In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic monomeric building blocks for RNA. Deoxyribonucleotides, formed by reducing ribonucleotides with the enzyme ribonucleotide reductase (RNR), are essential building blocks for DNA. There are several differences between DNA deoxyribonucleotides and RNA ribonucleotides. Successive nucleotides are linked together via phosphodiester bonds.

<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:

A salvage pathway is a pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. The term often refers to nucleotide salvage in particular, in which nucleotides are synthesized from intermediates in their degradative pathway.

Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage. This process is activated during rest periods following the Cori cycle, in the liver, and also activated by insulin in response to high glucose levels.

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

Glycogen phosphorylase is one of the phosphorylase enzymes. Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. Glycogen phosphorylase is also studied as a model protein regulated by both reversible phosphorylation and allosteric effects.

<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 ribonucleoside monophosphate. Guanosine monophosphate is commercially produced by microbial fermentation.

<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">Nucleic acid metabolism</span> Process

Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.

Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.

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.

<span class="mw-page-title-main">Purine nucleotide cycle</span>

The Purine Nucleotide Cycle is a metabolic pathway in protein metabolism requiring the amino acids aspartate and glutamate. The cycle is used to regulate the levels of adenine nucleotides, in which ammonia and fumarate are generated. AMP coverts into IMP and the byproduct ammonia. IMP converts to S-AMP (adenylosuccinate), which then coverts to AMP and the byproduct fumarate. The fumarate goes on to produce ATP (energy) via oxidative phosphorylation as it enters the Krebs Cycle and then the Electron Transport Chain. Lowenstein first described this pathway and outlined its importance in processes including amino acid catabolism and regulation of flux through glycolysis and the Krebs cycle.

<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.

<span class="mw-page-title-main">Ribose</span> Group of simple sugar and carbohydrate compounds

Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, d-ribose, is a component of the ribonucleotides from which RNA is built, and so this compound is necessary for coding, decoding, regulation and expression of genes. It has a structural analog, deoxyribose, which is a similarly essential component of DNA. l-ribose is an unnatural sugar that was first prepared by Emil Fischer and Oscar Piloty in 1891. It was not until 1909 that Phoebus Levene and Walter Jacobs recognised that d-ribose was a natural product, the enantiomer of Fischer and Piloty's product, and an essential component of nucleic acids. Fischer chose the name "ribose" as it is a partial rearrangement of the name of another sugar, arabinose, of which ribose is an epimer at the 2' carbon; both names also relate to gum arabic, from which arabinose was first isolated and from which they prepared l-ribose.

References

  1. 1 2 3 4 5 6 7 Beavo JA, Brunton LL (September 2002). "Cyclic nucleotide research -- still expanding after half a century". Nat. Rev. Mol. Cell Biol. 3 (9): 710–8. doi:10.1038/nrm911. PMID   12209131. S2CID   33021271.
  2. 1 2 3 4 5 6 Newton RP, Smith CJ (September 2004). "Cyclic nucleotides". Phytochemistry. 65 (17): 2423–37. doi:10.1016/j.phytochem.2004.07.026. PMID   15381406.
  3. 1 2 3 4 5 Kaupp UB, Seifert R (July 2002). "Cyclic nucleotide-gated ion channels". Physiol. Rev. 82 (3): 769–824. CiteSeerX   10.1.1.319.7608 . doi:10.1152/physrev.00008.2002. PMID   12087135.
  4. ↑ Seifert, R. (2015). "cCMP and cUMP: emerging second messengers". Trends in Biochemical Sciences. 40 (1): 8–15. doi:10.1016/j.tibs.2014.10.008. PMID   25435399.
  5. 1 2 Gomelsky, Mark (2011). "cAMP, c-di-GMP, c-di-AMP, and now cGMP: bacteria use them all!". Molecular Microbiology. 79 (3): 562–565. doi:10.1111/j.1365-2958.2010.07514.x. PMC   3079424 . PMID   21255104.
  6. ↑ Nelson, David; Michael Cox (2008). Lehninger Principles of Biochemistry (Fifth ed.). New York, NY: W.H. Freeman and Company. ISBN   978-0-7167-7108-1.
  7. ↑ "Nucleotide Numbering". Tulane University. Retrieved 9 May 2013.
  8. ↑ "National Library of Medicine - Medical Subject Headings, Adenylyl Cyclase".
  9. 1 2 Flacke JP, Flacke H, Appukuttan A, et al. (February 2013). "Type 10 soluble adenylyl cyclase is overexpressed in prostate carcinoma and controls proliferation of prostate cancer cells". J. Biol. Chem. 288 (5): 3126–35. doi: 10.1074/jbc.M112.403279 . PMC   3561535 . PMID   23255611.
  10. 1 2 Bender AT, Beavo JA (September 2006). "Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use". Pharmacol. Rev. 58 (3): 488–520. doi:10.1124/pr.58.3.5. PMID   16968949. S2CID   7397281.
  11. ↑ Reinecke D, Schwede F, Genieser HG, Seifert R (2013). "Analysis of substrate specificity and kinetics of cyclic nucleotide phosphodiesterases with N'-methylanthraniloyl-substituted purine and pyrimidine 3',5'-cyclic nucleotides by fluorescence spectrometry". PLOS ONE. 8 (1): e54158. Bibcode:2013PLoSO...854158R. doi: 10.1371/journal.pone.0054158 . PMC   3544816 . PMID   23342095.
  12. ↑ Rehmann H, Wittinghofer A, Bos JL (January 2007). "Capturing cyclic nucleotides in action: snapshots from crystallographic studies". Nat. Rev. Mol. Cell Biol. 8 (1): 63–73. doi:10.1038/nrm2082. PMID   17183361. S2CID   7216248.
  13. 1 2 Wolter S, Golombek M, Seifert R (December 2011). "Differential activation of cAMP- and cGMP-dependent protein kinases by cyclic purine and pyrimidine nucleotides". Biochem. Biophys. Res. Commun. 415 (4): 563–6. doi:10.1016/j.bbrc.2011.10.093. PMID   22074826.
  14. 1 2 Bridges, D; Fraser ME; Moorhead GB (2005). "Cyclic nucleotide binding proteins in the Arabidopsis thaliana and Oryza sativa genomes". BMC Bioinformatics. 6: 6. doi:10.1186/1471-2105-6-6. PMC   545951 . PMID   15644130.
  15. 1 2 Eckly-Michel A, Martin V, Lugnier C (September 1997). "Involvement of cyclic nucleotide-dependent protein kinases in cyclic AMP-mediated vasorelaxation". Br. J. Pharmacol. 122 (1): 158–64. doi:10.1038/sj.bjp.0701339. PMC   1564898 . PMID   9298542.
  16. ↑ Holz GG (January 2004). "Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell". Diabetes. 53 (1): 5–13. doi:10.2337/diabetes.53.1.5. PMC   3012130 . PMID   14693691.
  17. ↑ Zhou Y, Zhang X, Ebright RH (July 1993). "Identification of the activating region of catabolite gene activator protein (CAP): isolation and characterization of mutants of CAP specifically defective in transcription activation". Proc. Natl. Acad. Sci. U.S.A. 90 (13): 6081–5. Bibcode:1993PNAS...90.6081Z. doi: 10.1073/pnas.90.13.6081 . PMC   46871 . PMID   8392187.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ↑ Meiklejohn AL, Gralla JD (December 1985). "Entry of RNA polymerase at the lac promoter". Cell. 43 (3 Pt 2): 769–76. doi: 10.1016/0092-8674(85)90250-8 . PMID   3907860.
  19. ↑ Desch M, Schinner E, Kees F, Hofmann F, Seifert R, Schlossmann J (September 2010). "Cyclic cytidine 3',5'-monophosphate (cCMP) signals via cGMP kinase I". FEBS Lett. 584 (18): 3979–84. doi: 10.1016/j.febslet.2010.07.059 . PMID   20691687.
  20. ↑ Beavo, Joseph; Sharron Francis; Miles Houslay (2010). Cyclic Nucleotide Phosphodiesterases in Health and Disease . Boca Raton, FL: CRC Press. p.  546. ISBN   9780849396687.
  21. ↑ Sutherland, Earl; Robison GA; Butcher RW (1968). "Some aspects of the biological role of adenosine 3',5'-monophosphate (cyclic AMP)". Circulation. 37 (2): 279–306. doi: 10.1161/01.CIR.37.2.279 .
  22. ↑ Lincoln, TM; Cornwell TL (1991). "Towards an understanding of the mechanism of action of cyclic AMP and cyclic GMP in smooth muscle relaxation". Blood Vessels. 28 (1–3): 129–37. doi:10.1159/000158852. PMID   1848122.
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.