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cAMP-dependent pathway

January 01, 1970


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.[1]

Discovery edit

cAMP was discovered by Earl Sutherland and Ted Rall in the mid 1950s. cAMP is considered a secondary messenger along with Ca2+. Sutherland won the Nobel Prize in 1971 for his discovery of the mechanism of action of epinephrine in glycogenolysis, that requires cAMP as secondary messenger.[2]

Mechanism edit

G protein-coupled receptors (GPCRs) are a large family of integral membrane proteins that respond to a variety of extracellular stimuli. Each GPCR binds to and is activated by a specific ligand stimulus that ranges in size from small molecule catecholamines, lipids, or neurotransmitters to large protein hormones.[3] When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor that is transmitted to an attached intracellular heterotrimeric G protein complex. The Gs alpha subunit of the stimulated G protein complex exchanges GDP for GTP and is released from the complex.[4]

In a cAMP-dependent pathway, the activated Gs alpha subunit binds to and activates an enzyme called adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP).[5] Increases in concentration of the second messenger cAMP may lead to the activation of

The PKA enzyme is also known as cAMP-dependent enzyme because it gets activated only if cAMP is present. Once PKA is activated, it phosphorylates a number of other proteins including:[10]

  • enzymes that convert glycogen into glucose
  • enzymes that promote muscle contraction in the heart leading to an increase in heart rate
  • transcription factors, which regulate gene expression
  • also phosphorylate AMPA receptors[11]

Specificity of signaling between a GPCR and its ultimate molecular target through a cAMP-dependent pathway may be achieved through formation of a multiprotein complex that includes the GPCR, adenylyl cyclase, and the effector protein.[12]

Importance edit

Main article: function of cAMP-dependent protein kinase

In humans, cAMP works by activating protein kinase A (PKA, cAMP-dependent protein kinase), one of the first few kinases discovered. It has four sub-units two catalytic and two regulatory. cAMP binds to the regulatory sub-units.[13] It causes them to break apart from the catalytic sub-units. The catalytic sub-units make their way in to the nucleus to influence transcription. Further effects mainly depend on cAMP-dependent protein kinase, which vary based on the type of cell.

cAMP-dependent pathway is necessary for many living organisms and life processes. Many different cell responses are mediated by cAMP; these include increase in heart rate, cortisol secretion, and breakdown of glycogen and fat. cAMP is essential for the maintenance of memory in the brain, relaxation in the heart, and water absorbed in the kidney.[14] This pathway can activate enzymes and regulate gene expression. The activation of preexisting enzymes is a much faster process, whereas regulation of gene expression is much longer and can take up to hours. The cAMP pathway is studied through loss of function (inhibition) and gain of function (increase) of cAMP.

If cAMP-dependent pathway is not controlled, it can ultimately lead to hyper-proliferation, which may contribute to the development and/or progression of cancer.

Activation edit

Activated GPCRs cause a conformational change in the attached G protein complex, which results in the Gs alpha subunit's exchanging GDP for GTP and separation from the beta and gamma subunits. The Gs alpha subunit, in turn, activates adenylyl cyclase, which quickly converts ATP into cAMP. This leads to the activation of the cAMP-dependent pathway. This pathway can also be activated downstream by directly activating adenylyl cyclase or PKA.

Molecules that activate cAMP pathway include:

  • cholera toxin - increases cAMP levels
  • forskolin - a diterpene natural product that activates adenylyl cyclase
  • caffeine and theophylline inhibit cAMP phosphodiesterase, which degrades cAMP - thus enabling higher levels of cAMP than would otherwise be had.
  • bucladesine (dibutyryl cAMP, db cAMP) - also a phosphodiesterase inhibitor
  • pertussis toxin, which increases cAMP levels by inhibiting Gi to its GDP (inactive) form. This leads to an increase in adenylyl cyclase activity, thereby increasing cAMP levels, which can lead to an increase in insulin and therefore hypoglycemia

Deactivation edit

The Gs alpha subunit slowly catalyzes the hydrolysis of GTP to GDP, which in turn deactivates the Gs protein, shutting off the cAMP pathway. The pathway may also be deactivated downstream by directly inhibiting adenylyl cyclase or dephosphorylating the proteins phosphorylated by PKA.

Molecules that inhibit the cAMP pathway include:

  • cAMP phosphodiesterase converts cAMP into AMP by breaking the phosphodiester bond, in turn reducing the cAMP levels
  • Gi protein, which is a G protein that inhibits adenylyl cyclase, reducing cAMP levels.

[15]

References edit

  1. ^ Bruce Alberts; Alexander Johnson; Julian Lewis; Martin Raff; Dennis Bray; Karen Hopkin; Keith Roberts; Peter Walter (2004). Essential cell biology (2nd ed.). New York: Garland Science. ISBN 978-0-8153-3480-4.
  2. ^ Hofer, Aldebaran M.; Lefkimmiatis, Konstantinos (1 October 2007). "Extracellular Calcium and cAMP: Second Messengers as "Third Messengers"?". Physiology. 22 (5): 320–327. doi:10.1152/physiol.00019.2007. ISSN 1548-9213. PMID 17928545.
  3. ^ Willoughby, Debbie; Cooper, Dermot M. F. (1 July 2007). "Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains". Physiological Reviews. 87 (3): 965–1010. CiteSeerX 10.1.1.336.3746. doi:10.1152/physrev.00049.2006. ISSN 0031-9333. PMID 17615394.
  4. ^ Willoughby, Debbie; Cooper, Dermot M. F. (1 July 2007). "Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains". Physiological Reviews. 87 (3): 965–1010. CiteSeerX 10.1.1.336.3746. doi:10.1152/physrev.00049.2006. ISSN 0031-9333. PMID 17615394.
  5. ^ Hanoune J, Defer N (2001). "Regulation and role of adenylyl cyclase isoforms". Annu. Rev. Pharmacol. Toxicol. 41: 145–74. doi:10.1146/annurev.pharmtox.41.1.145. PMID 11264454.
  6. ^ 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.
  7. ^ Bos JL (December 2006). "Epac proteins: multi-purpose cAMP targets". Trends Biochem. Sci. 31 (12): 680–6. doi:10.1016/j.tibs.2006.10.002. PMID 17084085.
  8. ^ Simrick S (April 2013). "Popeye domain-containing proteins and stress-mediated modulation of cardiac pacemaking". Trends Cardiovasc. Med. 23 (7): 257–63. doi:10.1016/j.tcm.2013.02.002. PMC 4916994. PMID 23562093.
  9. ^ Meinkoth JL, Alberts AS, Went W, Fantozzi D, Taylor SS, Hagiwara M, Montminy M, Feramisco JR (November 1993). "Signal transduction through the cAMP-dependent protein kinase". Mol. Cell. Biochem. 127–128: 179–86. doi:10.1007/BF01076769. PMID 7935349. S2CID 24755283.
  10. ^ Walsh DA, Van Patten SM (December 1994). "Multiple pathway signal transduction by the cAMP-dependent protein kinase". FASEB J. 8 (15): 1227–36. doi:10.1096/fasebj.8.15.8001734. PMID 8001734. S2CID 45750089.
  11. ^ Man, Heng-Ye; Sekine-Aizawa, Yoko; Huganir, Richard L. (27 February 2007). "Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking through PKA phosphorylation of the Glu receptor 1 subunit". Proceedings of the National Academy of Sciences. 104 (9): 3579–3584. Bibcode:2007PNAS..104.3579M. doi:10.1073/pnas.0611698104. ISSN 0027-8424. PMC 1805611. PMID 17360685.
  12. ^ Davare MA, Avdonin V, Hall DD, Peden EM, Burette A, Weinberg RJ, Horne MC, Hoshi T, Hell JW (July 2001). "A β2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2". Science. 293 (5527): 98–101. doi:10.1126/science.293.5527.98. PMID 11441182.
  13. ^ Cheng, Xiaodong; Ji, Zhenyu; Tsalkova, Tamara; Mei, Fang (8 November 2016). "Epac and PKA: a tale of two intracellular cAMP receptors". Acta Biochimica et Biophysica Sinica. 40 (7): 651–662. doi:10.1111/j.1745-7270.2008.00438.x. ISSN 1672-9145. PMC 2630796. PMID 18604457.
  14. ^ Cheng, Xiaodong; Ji, Zhenyu; Tsalkova, Tamara; Mei, Fang (8 November 2016). "Epac and PKA: a tale of two intracellular cAMP receptors". Acta Biochimica et Biophysica Sinica. 40 (7): 651–662. doi:10.1111/j.1745-7270.2008.00438.x. ISSN 1672-9145. PMC 2630796. PMID 18604457.
  15. ^ Kamenetsky, Margarita; Middelhaufe, Sabine; Bank, Erin M.; Levin, Lonny R.; Buck, Jochen; Steegborn, Clemens (September 2006). "Molecular Details of cAMP Generation in Mammalian Cells: A Tale of Two Systems". Journal of Molecular Biology. 362 (4): 623–639. doi:10.1016/j.jmb.2006.07.045. PMC 3662476. PMID 16934836.

January 01, 1970
camp, dependent, pathway, this, article, needs, additional, citations, verification, please, help, improve, this, article, adding, citations, reliable, sources, unsourced, material, challenged, removed, find, sources, camp, dependent, pathway, news, newspapers. This article needs additional citations for verification Please help improve this article by adding citations to reliable sources Unsourced material may be challenged and removed Find sources CAMP dependent pathway news newspapers books scholar JSTOR May 2008 Learn how and when to remove this message 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 1 Contents 1 Discovery 2 Mechanism 3 Importance 4 Activation 5 Deactivation 6 ReferencesDiscovery editcAMP was discovered by Earl Sutherland and Ted Rall in the mid 1950s cAMP is considered a secondary messenger along with Ca2 Sutherland won the Nobel Prize in 1971 for his discovery of the mechanism of action of epinephrine in glycogenolysis that requires cAMP as secondary messenger 2 Mechanism editG protein coupled receptors GPCRs are a large family of integral membrane proteins that respond to a variety of extracellular stimuli Each GPCR binds to and is activated by a specific ligand stimulus that ranges in size from small molecule catecholamines lipids or neurotransmitters to large protein hormones 3 When a GPCR is activated by its extracellular ligand a conformational change is induced in the receptor that is transmitted to an attached intracellular heterotrimeric G protein complex The Gs alpha subunit of the stimulated G protein complex exchanges GDP for GTP and is released from the complex 4 In a cAMP dependent pathway the activated Gs alpha subunit binds to and activates an enzyme called adenylyl cyclase which in turn catalyzes the conversion of ATP into cyclic adenosine monophosphate cAMP 5 Increases in concentration of the second messenger cAMP may lead to the activation of cyclic nucleotide gated ion channels 6 exchange proteins activated by cAMP EPAC 7 such as RAPGEF3 popeye domain containing proteins Popdc 8 an enzyme called protein kinase A PKA 9 The PKA enzyme is also known as cAMP dependent enzyme because it gets activated only if cAMP is present Once PKA is activated it phosphorylates a number of other proteins including 10 enzymes that convert glycogen into glucose enzymes that promote muscle contraction in the heart leading to an increase in heart rate transcription factors which regulate gene expression also phosphorylate AMPA receptors 11 Specificity of signaling between a GPCR and its ultimate molecular target through a cAMP dependent pathway may be achieved through formation of a multiprotein complex that includes the GPCR adenylyl cyclase and the effector protein 12 Importance editMain article function of cAMP dependent protein kinase In humans cAMP works by activating protein kinase A PKA cAMP dependent protein kinase one of the first few kinases discovered It has four sub units two catalytic and two regulatory cAMP binds to the regulatory sub units 13 It causes them to break apart from the catalytic sub units The catalytic sub units make their way in to the nucleus to influence transcription Further effects mainly depend on cAMP dependent protein kinase which vary based on the type of cell cAMP dependent pathway is necessary for many living organisms and life processes Many different cell responses are mediated by cAMP these include increase in heart rate cortisol secretion and breakdown of glycogen and fat cAMP is essential for the maintenance of memory in the brain relaxation in the heart and water absorbed in the kidney 14 This pathway can activate enzymes and regulate gene expression The activation of preexisting enzymes is a much faster process whereas regulation of gene expression is much longer and can take up to hours The cAMP pathway is studied through loss of function inhibition and gain of function increase of cAMP If cAMP dependent pathway is not controlled it can ultimately lead to hyper proliferation which may contribute to the development and or progression of cancer Activation editActivated GPCRs cause a conformational change in the attached G protein complex which results in the Gs alpha subunit s exchanging GDP for GTP and separation from the beta and gamma subunits The Gs alpha subunit in turn activates adenylyl cyclase which quickly converts ATP into cAMP This leads to the activation of the cAMP dependent pathway This pathway can also be activated downstream by directly activating adenylyl cyclase or PKA Molecules that activate cAMP pathway include cholera toxin increases cAMP levels forskolin a diterpene natural product that activates adenylyl cyclase caffeine and theophylline inhibit cAMP phosphodiesterase which degrades cAMP thus enabling higher levels of cAMP than would otherwise be had bucladesine dibutyryl cAMP db cAMP also a phosphodiesterase inhibitor pertussis toxin which increases cAMP levels by inhibiting Gi to its GDP inactive form This leads to an increase in adenylyl cyclase activity thereby increasing cAMP levels which can lead to an increase in insulin and therefore hypoglycemiaDeactivation editThe Gs alpha subunit slowly catalyzes the hydrolysis of GTP to GDP which in turn deactivates the Gs protein shutting off the cAMP pathway The pathway may also be deactivated downstream by directly inhibiting adenylyl cyclase or dephosphorylating the proteins phosphorylated by PKA Molecules that inhibit the cAMP pathway include cAMP phosphodiesterase converts cAMP into AMP by breaking the phosphodiester bond in turn reducing the cAMP levels Gi protein which is a G protein that inhibits adenylyl cyclase reducing cAMP levels 15 References edit Bruce Alberts Alexander Johnson Julian Lewis Martin Raff Dennis Bray Karen Hopkin Keith Roberts Peter Walter 2004 Essential cell biology 2nd ed New York Garland Science ISBN 978 0 8153 3480 4 Hofer Aldebaran M Lefkimmiatis Konstantinos 1 October 2007 Extracellular Calcium and cAMP Second Messengers as Third Messengers Physiology 22 5 320 327 doi 10 1152 physiol 00019 2007 ISSN 1548 9213 PMID 17928545 Willoughby Debbie Cooper Dermot M F 1 July 2007 Organization and Ca2 Regulation of Adenylyl Cyclases in cAMP Microdomains Physiological Reviews 87 3 965 1010 CiteSeerX 10 1 1 336 3746 doi 10 1152 physrev 00049 2006 ISSN 0031 9333 PMID 17615394 Willoughby Debbie Cooper Dermot M F 1 July 2007 Organization and Ca2 Regulation of Adenylyl Cyclases in cAMP Microdomains Physiological Reviews 87 3 965 1010 CiteSeerX 10 1 1 336 3746 doi 10 1152 physrev 00049 2006 ISSN 0031 9333 PMID 17615394 Hanoune J Defer N 2001 Regulation and role of adenylyl cyclase isoforms Annu Rev Pharmacol Toxicol 41 145 74 doi 10 1146 annurev pharmtox 41 1 145 PMID 11264454 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 Bos JL December 2006 Epac proteins multi purpose cAMP targets Trends Biochem Sci 31 12 680 6 doi 10 1016 j tibs 2006 10 002 PMID 17084085 Simrick S April 2013 Popeye domain containing proteins and stress mediated modulation of cardiac pacemaking Trends Cardiovasc Med 23 7 257 63 doi 10 1016 j tcm 2013 02 002 PMC 4916994 PMID 23562093 Meinkoth JL Alberts AS Went W Fantozzi D Taylor SS Hagiwara M Montminy M Feramisco JR November 1993 Signal transduction through the cAMP dependent protein kinase Mol Cell Biochem 127 128 179 86 doi 10 1007 BF01076769 PMID 7935349 S2CID 24755283 Walsh DA Van Patten SM December 1994 Multiple pathway signal transduction by the cAMP dependent protein kinase FASEB J 8 15 1227 36 doi 10 1096 fasebj 8 15 8001734 PMID 8001734 S2CID 45750089 Man Heng Ye Sekine Aizawa Yoko Huganir Richard L 27 February 2007 Regulation of a amino 3 hydroxy 5 methyl 4 isoxazolepropionic acid receptor trafficking through PKA phosphorylation of the Glu receptor 1 subunit Proceedings of the National Academy of Sciences 104 9 3579 3584 Bibcode 2007PNAS 104 3579M doi 10 1073 pnas 0611698104 ISSN 0027 8424 PMC 1805611 PMID 17360685 Davare MA Avdonin V Hall DD Peden EM Burette A Weinberg RJ Horne MC Hoshi T Hell JW July 2001 A b2 adrenergic receptor signaling complex assembled with the Ca2 channel Cav1 2 Science 293 5527 98 101 doi 10 1126 science 293 5527 98 PMID 11441182 Cheng Xiaodong Ji Zhenyu Tsalkova Tamara Mei Fang 8 November 2016 Epac and PKA a tale of two intracellular cAMP receptors Acta Biochimica et Biophysica Sinica 40 7 651 662 doi 10 1111 j 1745 7270 2008 00438 x ISSN 1672 9145 PMC 2630796 PMID 18604457 Cheng Xiaodong Ji Zhenyu Tsalkova Tamara Mei Fang 8 November 2016 Epac and PKA a tale of two intracellular cAMP receptors Acta Biochimica et Biophysica Sinica 40 7 651 662 doi 10 1111 j 1745 7270 2008 00438 x ISSN 1672 9145 PMC 2630796 PMID 18604457 Kamenetsky Margarita Middelhaufe Sabine Bank Erin M Levin Lonny R Buck Jochen Steegborn Clemens September 2006 Molecular Details of cAMP Generation in Mammalian Cells A Tale of Two Systems Journal of Molecular Biology 362 4 623 639 doi 10 1016 j jmb 2006 07 045 PMC 3662476 PMID 16934836 Portal nbsp 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