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G Protein Coupled Receptors


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#1 O)))

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Posted 23 July 2009 - 02:00 AM

Im working on G protein coupled receptors and their downstream signalling pathways, and altered functioning in neurodegeneration.
Specifically, im interested in how alterations in the levels of G alpha subunits effect signalling. One issue im having trouble understanding is how changes in the level of the G alpha subunit may affect the functioning of the associated betagamma subunit.

The alpha subunit itself is inherently a guanine nucleotide dissociation inhibitor (GDI), a property which in basal conditions keeps it associated with the betagamma subunit. Receptor activation results in GDP release from G alpha, and subsequent GTP binding, allowing both the alpha and beta subunits to activate various effector pathways.

Thus, if youve an increased expression of the alpha subunit, does this imply greater adherence to betagamma subunits, and thus decreased betagamma mediated signalling?

Obviously im over-simplifying here. Ive searched for over expression studies that might address this, but had no luck. It may well vary on a case by case basis depending on other associated factors (G alpha to betagamma ratio, local GTP concentration etc).

Sorry if its not well explaing, jsut something thats been puzzling me lately
Interested in hearing opinions on this.
Thanks.

#2 polyfractal

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Posted 25 July 2009 - 11:31 AM

This is my purely theoretical opinion, but I think you would see an increase in Galpha signaling and a decrease in betagamma signaling.

An increase in Galpha should sequester more free betagamma subunits, reducing their signaling capability. At the same time, it is also likely that there will be more alpha subunits than betagamma subunits available for sequestering, so the free alpha subunits will continue to signal. It is also possible you have introduced more alpha than there are receptors to bind to, meaning a portion of the alpha pool may be permanently "on" since they are never reassociated with receptors to deactivate after the signaling cascade has run its course.

That said, there are many compounding factors. Perhaps the alpha subunit degradation pathway increases in response so the excess alpha is degraded instead of signaling. Alternatively, perhaps betagamma mimicks will bind the excess alpha subunit and alter the signaling.

#3 O)))

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Posted 28 July 2009 - 07:49 AM

Thanks for the response. I was thinking along these lines also.
I think a key issue here, as youve mentioned, is where these additional alpha subunits end up, and whether there are sufficient betagamma subunits to associate with them to form heterotrimers. Theres been some work done on antibodies which can detect the activation state of g protein subunits (ie associated or dissociated), which would answer the question nicely, but theyre not commercially available unfortunately.
http://www.fasebj.or.../full/22/6/1924

I was hoping this might be something that had been established, but it seems not to be, and as youve said, its likely to be subject to many other factors.
No easy answers im afraid!!!

#4 J-Erny

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Posted 30 January 2010 - 12:22 AM

Hello:

About G protein we have descrived by immunofluorescence to 1a-AR higher density of alpha1a-AR staining (GII 121.38 vs. GIII 146.03 p-value = 0.05), statistically significant in regard of grade in Oligodendrogliomas.

I am interested in this G protein because we think that there are overexpression in some cases of oligodendrogliomas but i can not convince people enough already.

http://www.diagnosti...ontent/3/S1/S26

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J-Erny

Edited by J-Erny, 30 January 2010 - 12:26 AM.





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