I'm looking at signalling in a receptor and using phosphorylation of ERK1/2 as a readout in HEK-293 cells stably expressing the receptor. In combination with a ligand specific for the receptor, I am consistently finding that at lower concentrations of the ligand, the allosteric modulator significantly enhances phosphorylation of ERK1/2 but at higher concentrations of the ligand this is not the case and the response is almost entirely depleted. I'm wondering if this is a feature of allosteric modulation as so far I have not found anything corroborating this finding in the literature?
You might consider the idea that the lack of phosphorylation turns off the receptor when the ligand concentration is high, but the occurrence of phosphorylation events turns on the receptor when the ligand concentration is low.
The orthosteric ligand (without allosteric ligand) could activate a different kind of receptor or inhibit ERK directly at high concentration but, probably, you have already checked this out, don`t you?
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