CAMP dependent pathway

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.cite book | author = Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Dennis Bray, Karen Hopkin, Keith Roberts, Peter Walter | authorlink = | editor = | others = | title = Essential cell biology | edition = 2 edition | language = | publisher = Garland Science | location = New York | year = 2004 | origyear = | pages = | quote = | isbn = 0-8153-3480-X | oclc = | doi = | url = | accessdate = ]

Mechanism

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

In a cAMP dependent pathway, the activated G_s alpha subunit binds to and activates an enzyme called adenylyl cyclase which in turn catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP).cite journal | author = Hanoune J, Defer N | title = Regulation and role of adenylyl cyclase isoforms | journal = Annu. Rev. Pharmacol. Toxicol. | volume = 41 | issue = | pages = 145–74 | year = 2001 | pmid = 11264454 | doi = 10.1146/annurev.pharmtox.41.1.145 | url = | accessdate = ] Increases in concentration of the second messenger cAMP may lead to the activation of
* cyclic nucleotide-gated ion channels,cite journal | author = Kaupp UB, Seifert R | title = Cyclic nucleotide-gated ion channels | journal = Physiol. Rev. | volume = 82 | issue = 3 | pages = 769–824 | year = 2002 | month = July | pmid = 12087135 | doi = 10.1152/physrev.00008.2002 | url = | accessdate = ]
* exchange proteins activated by cAMP (EPAC)cite journal | author = Bos JL | title = Epac proteins: multi-purpose cAMP targets | journal = Trends Biochem. Sci. | volume = 31 | issue = 12 | pages = 680–6 | year = 2006 | month = December | pmid = 17084085 | doi = 10.1016/j.tibs.2006.10.002 | url = | accessdate = ] such as RAPGEF3, or
* an enzyme called protein kinase A (PKA).cite journal | author = Meinkoth JL, Alberts AS, Went W, Fantozzi D, Taylor SS, Hagiwara M, Montminy M, Feramisco JR | title = Signal transduction through the cAMP-dependent protein kinase | journal = Mol. Cell. Biochem. | volume = 127-128 | issue = | pages = 179–86 | year = 1993 | month = November | pmid = 7935349 | doi = 10.1007/BF01076769 | url = | accessdate = ]

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:cite journal | author = Walsh DA, Van Patten SM | title = Multiple pathway signal transduction by the cAMP-dependent protein kinase | journal = FASEB J. | volume = 8 | issue = 15 | pages = 1227–36 | year = 1994 | month = December | pmid = 8001734 | doi = | url = http://www.fasebj.org/cgi/content/abstract/8/15/1227 | accessdate = ]
* enzymes which converts glycogen into glucose
* enzymes which promotes muscle contraction in heart leading to an increase in heart rate
* transcription factors which regulated gene expression

Specificity of signaling between a GPCR and its ultimate molecular target through a cAMP dependent pathway may be achieved through formation of a multi protein complex which includes the GPCR, adenylyl cyclase, and the effector protein.cite journal | author = Davare MA, Avdonin V, Hall DD, Peden EM, Burette A, Weinberg RJ, Horne MC, Hoshi T, Hell JW | title = A β₂ adrenergic receptor signaling complex assembled with the Ca²⁺ channel Cav1.2 | journal = Science (journal) | volume = 293 | issue = 5527 | pages = 98–101 | year = 2001 | month = July | pmid = 11441182 | doi = 10.1126/science.293.5527.98 | url = | accessdate = ]

Importance

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.

This pathway can activate enzymes and regulate gene expression. The activation of preexisting enzymes is a much faster process while 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

Activated GPCRs cause a conformational change in the attached G protein complex which results in the G_s alpha subunit exchanging GTP for GDP and separation from the beta and gamma subunits. The G_s 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 - increase cAMP levels
* forskolin - a diterpine natural product that activates adenylyl cyclase.
* caffeine and theophylline inhibit cAMP phosphodiesterase which leads to an activation of G proteins that result in the activation of the cAMP pathway
* bucladesine (dibutyryl cAMP, db cAMP) - also a phosphodiesterase inhibitor

Deactivation

The G_s alpha subunit slowly catalyzes the hydrolysis of GTP to GDP which in turn deactivates the G_s 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 cAMP pathway include:
* cAMP phosphodiesterase - has an activity opposite to kinase, therefore it dephospohorylates cAMP into AMP, reducing the cAMP levels.
* G_i protein - inhibitory G protein that inhibits adenylyl cyclase, reducing cAMP levels
* pertussis toxin - decrease cAMP level

References

External links

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