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In my biochem course, we learned that GPCR receptors trigger a phosphorylation cascade, with the end result being a large amplification of the signal in the form of cAMP. We never studied any particular GPCR individually, but we were told that GPCRs always end in the formation of a large amount of cAMP, which will go on to phosphorylate key targets that achieve the end result.

My question is as follows: If there are two GPCRs on the same cell membrane (let's say GPCR-A and GPCR-B triggered by substrates A and B respectively), how does the cell "know" which GPCR triggered the phosphorylation cascade if the end result is the same (large amount of cAMP). In theory, couldn't substrate B bind to GPCR-B and cause a phosphorylation cascade identical to that of GPCR-A, thus triggering GPCR-A's cellular response?

Is there some deeper specialization/uniqueness to each type of GPCR receptor that we didn't cover in my course? Does each GPCR produce a slightly different cascade that ends in something similar, but not exactly cAMP? Or is there some restriction, like each cell limited to only one GPCR (I would find this surprising, if this is the case)?

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First, it would be an oversimplification to say that GPCRs act only through increases in cytosolic cAMP. This is true for receptors coupled to Gs proteins, but there are other G proteins like Gi, Go and Gq which act differently [1].

Now, a cell can have receptors coupled to many different G proteins. Vascular smooth muscle, for instance, has Gs, Gi and Gq-coupled receptors [2]. Further, a cell can have different receptors coupling to G proteins of the same type (e.g., hepatocytes have glucagon and beta adrenergic receptors [3], which both couple to Gs).

In such situations, the effects of different hormones add up. The final effect is a function of the total cytosolic concentration of second messenger (e.g., cAMP). Thus glycogen breakdown in a hepatocyte depends on the overall effects of glucagon and epinephrine [3]. The hepatocyte has no way of 'knowing' which cAMP molecule was formed by which hormone.

References

  1. https://en.wikipedia.org/wiki/Heterotrimeric_G_protein

  2. https://cvphysiology.com/Blood%20Pressure/BP026

  3. https://www.nature.com/articles/emm2015122

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  • $\begingroup$ So, if cells have several different GPCRs of the same G-type but triggered by different substrates, the effects must be additive and can't be unique (i.e. the different substrates can't trigger entirely different cellular responses)? $\endgroup$
    – Sully Chen
    May 26 '20 at 9:01
  • $\begingroup$ @SullyChen No, I think. They can't be unique. Do you have any particular counter-example in mind? $\endgroup$
    – Adhish
    May 26 '20 at 10:10
  • $\begingroup$ I don't have a particular counter-example, but I can faintly remember a professor remarking that a single cell could have dozens (or hundreds? not quite sure) of GPCR proteins on its membrane, so I was curious if they were all duplicates of the same receptor or if they could possible all be unique. I think you've answered my question, thanks! $\endgroup$
    – Sully Chen
    May 26 '20 at 20:31

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