The GLP-1R receptor is currently a hot topic, both in pharmacology and in the popular news of the day. Understanding how this crucial receptor works at the molecular level is important in many regards, and the recent preprint from Manchanda and colleagues (Manchanda et al., 2025) provides new insights into how phosphorylation of key serines in the C-terminus appears to affect receptor mobility on the cell surface and coupling to intracellular signaling pathways.
Most models of receptor signaling go something like this: the agonist binds and activates the receptor, the activated receptor in turn signals through G-proteins and Beta arrestins until it is turned off. How is it turned off? Receptor kinases are recruited to the activated receptor where they phosphorylate key serine and threonines. This phosphorylated stretch of amino acids then recruits arrestin, which masks the receptor and blocks any further activation of G proteins (Gainetdinov et al., 2004).
Manchanda and colleagues recognized that the previous literature on phosphorylation of serines in the C-terminus of GLP-1R was somewhat contradictory, and re-examined the issue in a cell line that natively expresses the GLP-1R receptor and will, upon receptor activation, secrete insulin. In this cell line, INS-1 832/3 β-cells, they could study the GLP1 receptor in its native habitat. They knocked out the endogenous receptor and then reintroduced the human wild type GLP-1R receptor or versions in which the serines were removed from the C-terminus. A simple prediction, based on a simple model, would be that deletion of these serines would block receptor desensitization; the active receptor would no longer recruit arrestin, and the G protein signaling would be extended. Instead, using the cADDis cAMP biosensor, they found that when all of the serines are mutated, the receptor fails to signal through the Gs pathway. More surprisingly, they also see that the mutant receptor continues to recruit and activate the Borealis arrestin sensor.
When models don’t fit data, it’s the data that matters. This paper clearly shows us that we are still in for surprises, and that the INS-1 832/3 β-cells are an excellent vehicle for interrogating the receptor.
Essentially, all models are wrong, but some are useful
Gainetdinov, R. R., Premont, R. T., Bohn, L. M., Lefkowitz, R. J., & Caron, M. G. (2004). Desensitization of G protein-coupled receptors and neuronal functions. Annual Review of Neuroscience, 27(1), 107–144. https://doi.org/10.1146/annurev.neuro.27.070203.144206
Manchanda, Y., Wong, N., Milner, A., & Tomas, A. (2025). Glucagon-like peptide-1 receptor C-terminal tail phosphorylation determines signalling responses from pancreatic β-cells. In bioRxiv (p. 2025.11.01.686001). https://doi.org/10.1101/2025.11.01.686001