Hello,

it's hard to give the exact answer without any details on protein, its constitutively active form and agonist's mode of action.

But, in general, there are several possible explanations:

1) Constitutively active form of protein differs in its productivity from protein, which was activated by agonist. Constitutively active form of protein is the product of mutated gene, I suppose. So, mutation could alter not only the activation state of the protein, but its function also.

2) Existence of the constitutively activated protein will affect the whole regulatory network of the cell. It's hard to predict all the consequences.

3) In case the constitutively activated protein is delivered to the cell from outside, quality of the delivery system does matter.

4) Chemicals which are used as protein's function modulators often have some promiscuity of action. They can activate target protein and activate/inhibit many others, depends on given concentration.

Hi Pablo.

My two cents worth. First, there is no such thing as a specific agonist, they always interact with something else (something I painfully learned through hard practice), so, titrate you agonist (dose and time response curves). This might not clear the situation, for as the agonist gets metabolized, it might produce secondary effects, but it should provide better insight.

Second. The inherently active protein might interact with more targets than the native protein. It gets more time to do so and is also active while “in route” to its destination. Again, tritrate, but this time it´s harder to do since you can´t really tell the level of protein you are expressing. And that is another caveat, if the protein is highly overexpressed it could be inducing stress.

Third, how do the agonist and the activated protein interact? What happens if you use suboptimal doses of the agonist in the presence of the antagonist?

Best regards

Alejandro

Thanks for the answers. I am aware about the point that both of you mentioned. However my question is related to the physiological changes induced by this two mechanisms that seems to activate the same pathway just from different way.