We used to associate G proteins to most beneficial receptor functions & β-arrestin proteins to GPCRs internalization/signaling termination … But, do you think β-arrestins could contribute to GPCRs’ desired effects? Alternatively, could G proteins contribute to the development GPCRs’ side effects?
Hi guys,
the big problem in the field is the semantical imprecision. What do people really mean when referring to beta-arrestin-mediated signaling? What exactly is this? Is it arrestin-modulation of G protein signaling or arrestin signaling in the absence of G protein activity, ie truly G protein-indepedent signaling? For the latter there is no proof in the literature, however arrestin contribution to G protein signaling has been seen by many. If we use arrestin signaling for both scenarios, no surprise there is confusion. Inititially I liked the idea of arrestins signaling in their own right but I am afraid it is no more than a preconceived concept that does no longer hold since we have the tools to really challenge the concept. The signaling bias literature is full of papers with unsupported claims and I predict it will take years for our field to recover because some proponents of arrestin signaling are very protective of the arrestin transducer model. You cannot imagine that publishing my paper was close to impossible, I was caught in a mafia of people who tried everything to kill my paper. A nightmare for the first author, he left academic science, he was disgusted...
Anyway, when you read literature, be critical, don't believe every word of a high impact paper, look at the data and dare to come up with your own interpretation! We all have the same data in the bias field, what differs is our interpretation!
The definition of "desired" effect or "side" effect always depends on the context.
For example, glaucoma treatment with prostaglandins was also associated with the "side effect" of eyelash growth, which is why it is now separately used for "treatment" of hypotrichosis of eyelashes as "desired effect". Current use of sildenafil also developed from a "side" effect.
There is a lot of literature on biased GPCR signaling, where beta-arrestin signaling can be beneficial (e.g. metabolic studies from Jurgen Wess lab).
I'm familiar with Evi Kostenis' work, the experiments are nicely done.
Your question above does not indicate, that the G proteins are not involved at all, when we talk about beta-arrestin-mediated signaling.
But I agree that beta-arrestin signaling needs to be studied more carefully.
A great example are the opioid studies - respiratory depression and constipation were initially shown to be mediated by beta-arrestin 2 signaling and pain reduction by G proteins. Newer studies however show, that the first ones are independent of beta-arrestin 2 (PMID: 32052419, 30664663).
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