Talk:G protein-coupled receptor

Signal transduction

"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))

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)

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)

Structure

Should there not be mention of alpha, beta and gamma subunits, mention also of the G_s, G_i and G_q 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)

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.

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)

Removal of info on new GPCR structure (2007)

Resolved

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)

Any eukaryotes genomes without G-protein-coupled receptors?

The indtroductory paragraph states that GPCRs are found only in eukaryotes, and then lists major eukaryote taxa or representatives from these known to have GPCRs (plant, animal, fungi, protists). The impression is that GPCRs are thought to be a universal feature of Eukaryota, but this is not asserted explicitly.

Does anyone know of a counter-example? i.e. a eukaryote genome apparently lacking GPCRs?

Alternatively, are there likely examples of GPCRs known from any of the more exotic branches of the eukaryote tree? —Preceding unsigned comment added by Johnfravolda (talk • contribs) 16:12, 10 July 2009 (UTC)

Phosphorylation by cAMP-dependent protein kinases

In this section it reads:

"In fact any receptor causing an increase in PKA activity will cause increased amounts of this type of desensitisation of other receptors coupled to Go (e.g., dopamine receptor D2 activation may lead to β2-adrenoceptor desensitisation of this type).[22]"

The given reference does not say this as far as I can tell, also I could find no reference to Beta-2 AR Go coupling, although Gi coupling does occur as can be seen in the reference I added two sentences earlier.Repapetilto (talk) 22:01, 22 September 2009 (UTC)

Also I realized that doesnt even make sense since D2s are Gi coupled and would decrease cAMP, so I'm just going to change D2 to D1, which at least makes sense... the reference is still bad though.Repapetilto (talk) 22:01, 22 September 2009 (UTC)

D2 does activate phosphatase pathways such as extracellular signal-regulated kinases (ERK), independent of Gi / cAMP decrease, that might very well lead to heterologous receptor phosphorylation. Please do not change receptors names arbitrarily by gut-referencing... Also, too much and too specific detail is probably not good for the article and you might want to consider to be bold and taking such parts out. Cacycle (talk) 22:17, 22 September 2009 (UTC)

I think it works as a hypothetical example though. Repapetilto (talk) 12:18, 24 September 2009 (UTC)

Plants

I removed the section about plants since it was based on the GPCR1 and 2 found by the group publishing the Science paper on the topic, the claim has been disputed by several bioinformaticists. If you search on psi-blast for these proteins you find that they belong to the LanC-like super family, not GPCR. http://www.sciencemag.org/cgi/content/abstract/318/5852/914c this discovery has been questioned in future editions of Science (the original publisher of the article) as well as other journals. Until there has been a less controversial GPCR found in plants, I believe it is proper that it is removed from this article. 99.31.87.33 (talk) 03:04, 18 October 2009 (UTC)

Right. Uniprot tells about this protein: belongs to "Golgi pH regulator (TC 1.A.38) family" [1]. Any other plant "GPCR" [2] [3]? Biophys (talk) 18:02, 22 June 2010 (UTC)

Number of drugs

I found a current article Overington JP, Al-Lazikani B, Hopkins AL (December 2006). "How many drug targets are there?". Nat Rev Drug Discov 5 (12): 993–6. doi:10.1038/nrd2199. PMID 17139284.  Have no idea how to add it. It says that GPCRs make up 26.8% of current drugs, NOT half as mentioned in the article. HELP...

Thanks for catching this. The Overington paper does seem to be more definitive than the citation supporting the "around half" estimate. Therefore I have changed the text to read "approximately 30%" and added the citation that you found. Cheers. Boghog (talk) 05:57, 2 March 2010 (UTC)

Structure-Function Section

So I made that figure while filling out a study guide for comprehensive exams then cleaned it up to put it here. The text that goes along with it came from the same place, I didnt bother referencing anything at the time but its all good, just check the facts and add references, or else I'll do it later. Im kinda of busy right now though so... if someone else wants to do it that would be cool. Any questions just ask, I dont think it should be deleted though. Also if someone knows a better image format to reduce the thumbnail blur, that should also be changed...Repapetilto (talk) 05:05, 19 June 2010 (UTC)

I added a bunch more text, it has the same problems as mentioned above. I'll see about getting around to fixing that eventually.Repapetilto (talk) 08:29, 21 June 2010 (UTC)

What diseases and drugs ?

Intro says "G protein-coupled receptors are involved in many diseases, and are also the target of approximately 30% of all modern medicinal drugs[2][3]" but article, although large, doesn't seem to list or link to the diseases or drugs. Even Fillmore[2] only says "They account for the majority of best-selling drugs and about 40% of all prescription pharmaceuticals on the market. Notable examples include Eli Lilly’s Zyprexa, Schering-Plough’s Clarinex, GlaxoSmithKline’s Zantac, and Novartis’s Zelnorm."

Should we have a short section like Physiology about the diseases that could mention or link to the relevant drugs ? Rod57 (talk) 23:54, 1 March 2011 (UTC)

The challenge is that the list of drugs targeting GPCRs and the diseases these drugs treat is very diverse. The {{G protein-coupled receptors}} navbox that it is displayed at the end of the article has links to GPCR families and individual GPCRs. Many of these article contain information about drugs and/or the conditions they treat (see for example Dopamine receptor, histamine receptor, etc.) At the same time, it wouldn't hurt to add a short list or table of few well known GPCR drugs. For example here is a list of the top selling drugs by world wide sales. Starting at the top of the list, drugs that act at GPCRs include:

Drug	Therapeutic Class	Target GPCR
Clopidogrel	Platelet aggregation inhibitor	P2Y12
Olanzapine, Quetiapine, Risperidone	Antipsychotic	Several (including the dopamine and histamine receptors)
Montelukast	Anti-asthmatic	CYSLTR1
Valsartan	Antihypertensive	AGTR1

Cheers. Boghog (talk) 06:27, 2 March 2011 (UTC)