Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology

Round 1

Reviewer 1 Report

This review article entitled ‘Isoform-specific properties of Orai homologues in activation, downstream signaling, physiology and pathophysiology’ by Tiffner and Derler provides an excellent summary of different Orai isoforms. The manuscript is well-written and provides detailed mechanistic insights into channel activation, regulation and how that influences various aspects of cell function in health and disease.   

Author Response

Thanks!

Reviewer 2 Report

This is a very extensive and complete review of the isoform-specific properties, structure/function relationship, downstream signaling, and physiological as well as pathophysiological roles of the three Orai homologues. It is well-written and logically presented, from the isoform-specific structural properties, channel function, pH and redox sensitivity, downstream signaling, to the pharmacological and pathological profiles of three Orai homologues.

Especially, the authors did a great job in reviewing the structure/function relationship of Orai isoforms. However, the thorough descriptions could be a bit difficult to follow. Apart from the two figures provided in the current review, a summarized table to compare the point mutations, structural and functional impacts on calcium signaling (protein-protein interactions, gain of function, loss of function), and the pathological phenotypes of the three Orai homologues is suggested.

Author Response

We thank the reviewer for the suggestion to include some tables.

As requested we added several tables to the text and hope that they bring more clarity to the manuscript.