Biased Agonism or “Biaism” for Dummies: A Commentary

Round 1

Reviewer 1 Report

Ligand-dependent activation of cell surface receptors selectively elicits downstream signalling pathways that are transduced into a number of cellular responses. This simplified model of ligand-receptor signalling is indeed very different from physiological reality, and Bountin and Leprince convincingly challenged it in this manuscript. The authors point out a list of untapped qualities of G protein-coupled receptor signalling and appreciate variations of intracellular nature and stoichiometry of the ligands, receptors, and coupling proteins between cell and tissue systems. The pitfull knowledge of the ligand-receptor model acquired over the years, based on genuine 'physilogical-like' conditions is recognized here. In the context of this undeniable phenomenon, the authors consider many cautions necessary to apply and the experimental tools to set-up for future therapeutic research.

Overall, the manuscript is well written and will be of  strong interest to researchers studying receptology.

Author Response

We would like to thank the referre for her/his positive comments. We hope the paper in its final form will also interest the readers.

Reviewer 2 Report

Bias in GPCR is an important and not well-understood concept in GPCRs.

Fig 1 should be modified to explain what is shown in text better, at least make it more stronger and interesting rather than showing same or different ligands with letters A, B.

It seems different ligands are in A, while in B has same ligands, yet authors mention in A same or different cell and in B two different cells, but pictures in panel A and B look identical.

Please modify and strengthen the figure.

(A) ligand biased signaling (ligand 70 biaism) between two different agonists of the same receptors in a same or a different cell. (B) system 71 biased signaling (system biaism) of an agonist at a same receptor in two different cells. 

The role of allostery and structural dynamics is not or very poorly discussed and how it can play a role in bias and references should be given.

Authors should discuss how ligands and or other perturbers to the system, induce different dynamics and or allosteric pathways that lead to bias.

Fig 3 is too small relative to other figures and hard to read.

Can authors add another one or two figures to better explain other concepts.

Some recent work and reviews on bias should be included and mention what context this review provides 

https://www.nature.com/articles/nrd.2017.229

https://www.nature.com/articles/s41580-018-0049-3

How about structure based information of bias, modelling and simulations of dynamics and allostery?

Can revolution in AI and available structures of GPCR-G , arrestin etc complexes lead to better understanding of bias?

This should be discussed and references provided.

The English in this review needs to be more checked, and some sentences have strange structure.

Author Response

See attached file

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

I am ok with these revisions. 

I may still check on grammar and English a bit more.