cAMP dependent pathway

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Mechanism of cAMP dependent signaling. In this figure, the neurotransmitter epinephrine (adrenaline) and its receptor (pink) is used as an example. The activated receptor releases the Gs alpha protein (tan) from the beta amd gamma subunits (blue and green) in the heterotrimeric G-protein complex. The activated Gs alpha protein in turn activates adenylyl cyclase (purple) that converts ATP into the second messenger cAMP.
Mechanism of cAMP dependent signaling. In this figure, the neurotransmitter epinephrine (adrenaline) and its receptor (pink) is used as an example. The activated receptor releases the Gs alpha protein (tan) from the beta amd gamma subunits (blue and green) in the heterotrimeric G-protein complex. The activated Gs alpha protein in turn activates adenylyl cyclase (purple) that converts ATP into the second messenger cAMP.[1]

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.[2]

Contents

[edit] 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 Gs 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 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).[3] 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:[7]

  • 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.[8]

[edit] 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.

[edit] Activation

Activated GPCRs cause a conformational change in the attached G protein complex which results in the Gs alpha subunit exchanging GTP for GDP 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 - 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

[edit] Deactivation

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 cAMP pathway include:

  • cAMP phosphodiesterase - has an activity opposite to kinase, therefore it dephospohorylates cAMP into AMP, reducing the cAMP levels.
  • Gi protein - inhibitory G protein that inhibits adenylyl cyclase, reducing cAMP levels
  • pertussis toxin - decrease cAMP level

[edit] References

  1. ^ David S. Goodsell (October 2004). G Proteins: Relaying the Signal. Molecule of the Month. RCSB Protein Data Bank. Retrieved on 2008-05-25.
  2. ^ Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Dennis Bray, Karen Hopkin, Keith Roberts, Peter Walter (2004). Essential cell biology, 2 edition, New York: Garland Science. ISBN 0-8153-3480-X. 
  3. ^ 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. 
  4. ^ Kaupp UB, Seifert R (July 2002). "Cyclic nucleotide-gated ion channels". Physiol. Rev. 82 (3): 769–824. doi:10.1152/physrev.00008.2002. PMID 12087135. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ Walsh DA, Van Patten SM (December 1994). "Multiple pathway signal transduction by the cAMP-dependent protein kinase". FASEB J. 8 (15): 1227–36. PMID 8001734. 
  8. ^ 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 (journal) 293 (5527): 98–101. doi:10.1126/science.293.5527.98. PMID 11441182. 

[edit] External links