Talk:G protein-coupled receptor
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"The transduction of the signal through the membrane by the receptor is not completely understood. It is known that the inactive G protein is bound to the receptor in its inactive state. Once the ligand is recognized, the receptor shifts conformation and thus mechanically activates the G protein, which detatches from the receptor. The receptor can now either activate another G protein, or switch back to its inactive state. "
This is actually rather at odds with the current idea of GPCR activation.
The results of many hybrid and mutant receptor experiments, as well as evidence of agonist trafficking and constituitive activation, suggest a model of conformational selection rather than the conformational alteration described above (which is basically the same as the lock-and-key hypothesis of enzyme activation).
Current thinking is generally based around the Extended Ternary Complex Model (ETCM). In this model the GPCR and the G-protein exist in a continuum of states which can all occur in the absence of a ligand. Some of these states are active, some inactive. Some have the G-protein bound to the receptor, some do not.
Unfortunately this is difficult to express without a diagram. I'll post one here when I have time to find one.
The idea is basically that the GPCR and the G-protein continually fluctuate between active and inactive, bound and unbound states, very very quickly.
The majority of a receptor/G-protein population will (in the absence of ligands) be in inactive states, with a few being in active states. The addition of an agonist to this equilibrium shifts it in favour of the active, G-protein bound form of the receptor, which in turn creates conditions favourable for the active form of the G-protein. In other words an agonist binds very well to the active, G-protein bound form of the receptor and stabilises it (without an agonist this form has a very short half-life and is therefore only represented in a very small number of receptors in a population), giving time for the G-protein to be activated. Thus, rather than passively sitting there waiting for an agonist molecule to come along, the components of the signalling pathway are in a state of constant flux.
This model is necessary to explain the two phenomena mentioned above:
1) Agonist trafficking.
This name is given to the observed phenomenon that the same receptor can often activate different G-proteins in response to different agonists. Thus different effects can be mediated by different agonists via the same receptor.
2) Constituitive activation.
This is the situation in which GPCRs stimulate a response in the absence of any agonist. A good example of this is the GABA-B receptor. These receptors are active without the ligand (gamma-amino butyric acid, GABA) and considerably less active when it is introduced. The term which was coined for this behaviour is inverse agonism.
The model originally described makes it difficult to account for these phenomena - if the inactive receptor and G-protein are always bound then in a situation where a selection of G-proteins is available a full response to each of the various agonists trafficked by the receptor in question would not be possible (unless we posit further mechanisms in which an agonist can force the GPCR to detach from its current G-protein). Obviously if activation of the G-protein is dependent entirely upon ligand binding then constituitive activation would not be possible.
It would really help if there were some pictures on this page...--Dan 01:53, 21 January 2006 (UTC)
We need to get some structural detail with the alpha,beta, and gamma subunits on here. More detail on strucural rearrangements caused by GDP-GTP exchange. Does anyone know if you can use swissmol and Jmol as fair use for a picture upload of a GPCR?
Thanks for adding the image, however we need to label the subunits. Well done though. (Sterichinderance 07:04, 28 April 2006 (UTC))
Contents |
[edit] Receptor page
Receptor (proteomics) now contains a list of receptors. Please list any pages you know on that list, because it's presently a bit messy. JFW | T@lk 20:22, 14 Apr 2004 (UTC)
[edit] Move
This should be moved to G protein-coupled receptor as the proteins to which these receptors are linked are called "G proteins", not "G-proteins" (note the hyphen). As the move would require the fixing of more double redirects than I can presently manage alone, I'll just leave this note here. --David Iberri (talk) 23:21, 29 April 2006 (UTC)
- I tend to agree. Please consider listing at Wikipedia:Requested moves, which is meant for such non-trivial moves. User:Ceyockey (talk to me) 03:44, 30 April 2006 (UTC)
- I lost track of this for a while, but had a few extra minutes to do the page move myself. --David Iberri (talk) 17:40, 19 May 2006 (UTC)
[edit] Structure
Should there not be mention of alpha, beta and gamma subunits, mention also of the Gs, Gi and Gq types? --Copperman 08:29, 29 May 2006 (UTC)
- That's the G protein, not the GPCR --130.88.96.66 (talk) 02:00, 10 December 2007 (UTC)
[edit] Contradict
On the 7TM receptor it says that GPCRs are an important class of 7TM receptor. But here on the GPCR page, it says that 7TM receptor is a synonym for GPCR. Zargulon 10:25, 3 July 2006 (UTC)
- I suppose the 7TM Receptor article is the one in a question, not the 7TM receptor one. The second one serves as redirect to the G protein-coupled receptor article itself. (I would just boldly move the redirect to the 7TM Receptor name instead that G protein-coupled receptor, but I want to clarify the reason of confusion for those, who didn't find the target. --Reo ON | +++ 13:35, 10 July 2006 (UTC)
- I am not aware of any non G protein-coupled 7TM receptor, so I made 7TM receptor and 7TM Receptor into redirects to G protein-coupled receptor. Cacycle 03:09, 11 July 2006 (UTC)
- Look at bacteriorhodopsin as an example of a non G protein-coupled 7TM receptor. It is a photoreceptor that serves as an ion channel.
[edit] Redundant figures
There is little difference between FIG 1 and FIG2. The authors should DELETE Figure 2.
- I think you mean Figure 2 and 3 are similar. Figure 2 should probably be deleted since it is too small to garner any detail from--141.214.17.5 20:33, 19 October 2006 (UTC)
[edit] Removal of info on new GPCR structure (2007)
I am curious as to the reasoning behind this reversion edit, which removed information supported by a citation (albeit not in proper form). The reversion was accompanied by the edit summary "reverting last addition -- please propose on talk page". I was not the person who added the passage that was removed, I merely detected it on my watchlist and it caused a raised eyebrow. Thank you for the explanation. Regards --User:Ceyockey (talk to me) 11:09, 4 November 2007 (UTC)
- I think the reason for reverting the edit was that the interpretation of the new structure was highly misleading. It implied that homology models of human GPCRs based on the bovine rhodopsin structure would have large errors. What is far more relevant than species differences are sequence differences (which implies structure differences). If one wants to model a human GPCR that is more closely related in sequence to rhodopsin than the adrenergic receptor, it would be far better to use the bovine rhodopsin than the human adrenergic structure. If one wants to model a GPCR (human or bovine) that is closely related in sequence to the adrenergic receptor, it would be better to use the human adrenergic structure. Finally for GPCRs which are not close in sequence to either adrenergic receptor or rhodopsin, neither experimental template is likely to lead to a good model. I have re-inserted the information about the new GPCR structure with a somewhat different, and I hope more accurate interpretation. Cheers. Boghog2 13:42, 4 November 2007 (UTC)
- OK - It was mostly a matter of providing the newly published information with appropriate context and counterpoint so that it wouldn't be taken at face value. I've not yet read the manuscript myself, but I'm a bit more skeptical than most, I think, on the matter of sequence-structure relationship: structural similarity can appear in the face of sequence differences and vice versa (similar sequence, different structure) in the presence of differentiating post-translational modifications. --User:Ceyockey (talk to me) 14:04, 4 November 2007 (UTC)
