The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs
Round 1
Reviewer 1 Report
The article entitled "Fundamental role of bicarbonate transporters and associated enzymes carbonic anhydrases in maintaining ion and pH
homeostasis in non-secretory organs " is presented as a review
describing the fundamental role played by some of the bicarbonate
transporters and by some carbonic anydrase enzymes. As the authors
describe, the literature reports many informations on the role of this
ion and its transport proteins in multiple functional roles. Hence the
importance of the review which reports in a very well manner some
physiological aspects of the role of this ion. The figures show a good
resolution and are very well descriptive; the language is clear and the
text is well structured. The purpose of the article is to lay the
foundations for future understandings of the role of this ion in
physiological and pathological states, although there is still much to
explore. Therefore, for the topic addressed and for the way the article
was designed, it can be considered worthy of being published in the present
form.
Author Response
The article entitled "Fundamental role of bicarbonate transporters and associated enzymes carbonic anhydrases in maintaining ion and pH homeostasis in non-secretory organs " is presented as a review describing the fundamental role played by some of the bicarbonate transporters and by some carbonic anydrase enzymes. As the authors describe, the literature reports many informations on the role of this ion and its transport proteins in multiple functional roles. Hence the importance of the review which reports in a very well manner some physiological aspects of the role of this ion. The figures show a good resolution and are very well descriptive; the language is clear and the text is well structured. The purpose of the article is to lay the foundations for future understandings of the role of this ion in physiological and pathological states, although there is still much to explore. Therefore, for the topic addressed and for the way the article was designed, it can be considered worthy of being published in the present form.
Response: We really appreciate your comment.
Reviewer 2 Report
This review is a well-organized and useful readable state of the art about the role of the bicarbonate transporters and enzymes in ion homeostasis and pH regulation.
I would suggest integrating references with the more recent ones (as an example: PMID 31819195, DOI: 10.1038/s41416-019-0642-z) and, even though older but important PMID: 26124722, DOI: 10.3389/fphys.2015.00166, and other references (please accurately check).
Considering the long list of transport systems initially reported and then newly cited along the text, it would be useful an initial classification (for example in a table) in which it could be reported the protein name, the gene name and the protein mechanism.
Regarding the protein mechanism, please pay attention on the difference among transporters, pumps and channels (as an example: line 35…these transporters and channels….there are no channels reported! The sodium-potassium ATPase is a pump, not a channel. Moreover in the legends to figures authors always speak about channels referring to transporters: line 189 as an example. Please check in all the manuscript.
Attention has been paid also about the inappropriate use of the gene names: example, line 208: AE3 and SLC26A3….why do you use the protein name in one case and the name of a gene in the other case? Or line 114 SLC26A6….you must use the name of the protein; the gene name must be used if you are referring to the gene and not to the protein. Moreover, it should be avoided the confusion created using both gene and protein name starting by line 241.
Minor point:
line 13: “immune disorder”, “s” missing: disorders.
line 15: “Carbonic anhydrases are involved in mechanism of bicarbonate movement….” In the mechanism of transport?? Please explain.
line 27: “immune system” is not a function.
line28: “charged ions” uncharged ions do not exist, delete charged.
Line 33: “intracellular Na regulation”, substitute regulation with concentration.
Line 49: “pHi” please write intracellular pH in brackets as done for Cl concentration in line 154.
Line 63: (3)??? Or line 66: (5)???
Line 95: “DRA”, differently from the other proteins, in this case authors has not reported the transported ions and the mechanism (see for example line 39) in this point but in a next point (line 218).
Line 113: “phosphatidylinositol 4,5-bisphosphate (PIP2)” is not a protein.
Line 131: “….]. And…”, please correct.
Line 156: “….interact with high affinity for [Cl−]i.” high affinity is towards Cl, not [Cl−]i. See also line 159.
Line 156 and 158: “concentration of [Cl−]I” is wrong, please correct with concentration of Cl−i.
Line 159 : “affinity of [Cl−]i” is “affinity for Cl-i”.
Line 165: “and various other transporters”, the previous are not transporters but organs or systems.
Line 189: legend to figure 1 contains many errors: “channels” (are transporters); “involve in” delete and substitute with “:”; [pH]i is wrong, is pHi.
Line 229, legend to figure 2: once again authors use the word “channels” speaking about transporters. Authors use both protein and gene names (AE3 and SLC26A3) without an evident meaning. Please justify the choice to use different intensity of blue for all transporters but not for one that is green. What is it the pink circle?
Line 254: similar problem with this legend and legend of fig 5, line 328.
Line 329: “pH level” is wrong.
Line 337-338: modify this sentence detailing.
Line 341 does not sound well.
In the text is not reported a cross-reference to the table 1.
English grammar errors:
line 6: “Bicarbonate transporting mechanism” is “Bicarbonate transport mechanism”
line 15: “in mechanism” is “ in the mechanism”
line 18: “its” is “their”
Line 40: “ channels are” delete “s” from channels
Line 53: “in increased” substitute in with to
Line 56: “reveled” adjust with revealed
Line 94: the sentence “have been implicated to be involved with” sounds strange, please correct
Line 97: “transporters has”…have
Line 100 “will discuss” will be discussed
Line 116-117: “….dissociates from IP3R in the stimulating state such as activation of G protein-coupled receptor and released to cytosol”, rewrite this sentence
Line 118: “…has been unknown.” Do you mean: ….has been so far unknown?
Line 124: “transporters is”, are
Line 128: “decrease”, is “decreases”
Line 133: “which act….” Is “acts”
Line 138: “…residue” is “residues”
Line 141: “signaling molecules” is singular, molecule
Line 142: “ though” do you mean through?
Line 143: “therapeutic approaches” is “therapeutic approach”
Line 146: “its” is “their”
Line 150: “ through by”, is not correct
Line 152: “In accordance with,” is not correct
Line 152: “Cl- play”, “s” missing
Line 156:” which interact”, “s” missing
Line 160: “make”, “s” missing
Line 160: “can be suggest”, delete “be”
Line 163: too much “and”
Line 186: “in cellular network” is “in the cellular network”
Line 220: “null mice results” delete “s”
Line 276: “involves in” delete in
Line 294: “slice” is “splice”
Line 299: “ in basolateral membrane” is “ in the basolateral….”
Line 303: “maintain” add “s”
Line 336: “its associated” is “their”
Author Response
This review is a well-organized and useful readable state of the art about the role of the bicarbonate transporters and enzymes in ion homeostasis and pH regulation.
I would suggest integrating references with the more recent ones (as an example: PMID 31819195, DOI: 10.1038/s41416-019-0642-z) and, even though older but important PMID: 26124722, DOI: 10.3389/fphys.2015.00166, and other references (please accurately check).
Response: We appreciate your suggestion. We added more references to supplement section of carbonic anhydrases and SLC4 bicarbonate transporters.
Considering the long list of transport systems initially reported and then newly cited along the text, it would be useful an initial classification (for example in a table) in which it could be reported the protein name, the gene name and the protein mechanism.
Regarding the protein mechanism, please pay attention on the difference among transporters, pumps and channels (as an example: line 35…these transporters and channels… there are no channels reported! The sodium-potassium ATPase is a pump, not a channel. Moreover, in the legends to figures authors always speak about channels referring to transporters: line 189 as an example. Please check in all the manuscript.
Response: We appreciate your comments. The manuscript has been edited as you recommended.
Attention has been paid also about the inappropriate use of the gene names: example, line 208: AE3 and SLC26A3…. why do you use the protein name in one case and the name of a gene in the other case? Or line 114 SLC26A6…. you must use the name of the protein; the gene name must be used if you are referring to the gene and not to the protein. Moreover, it should be avoided the confusion created using both gene and protein name starting by line 241.
Response: We appreciate your comments. The manuscript has been edited as you recommended and the gene names have been marked as italic letters. The SLC26A6 was also used as protein name.
Minor point:
Response: We appreciate your comments. The manuscript has been edited as you recommended in minor point section.
line 13: “immune disorder”, “s” missing: disorders.
line 15: “Carbonic anhydrases are involved in mechanism of bicarbonate movement….” In the mechanism of transport?? Please explain.
Response: We appreciate your comments. The involvement between carbonic anhydrases and bicarbonate transport have been already explained in section 2 (Carbonic anhydrases: regulation of HCO3-). In abstract section, detailed explanation can be restricted in word limit. In section 2, we described that carbonic anhydrases accelerate HCO3- flux as mediators of HCO3- with regulation of cancer cell survival, cell migration, pH regulation, and enamel formation.
line 27: “immune system” is not a function.
Response: We appreciate your comments. The manuscript has been edited as immune system to immune cell differentiation.
line28: “charged ions” uncharged ions do not exist, delete charged.
The manuscript has been edited as you recommended.
Line 33: “intracellular Na regulation”, substitute regulation with concentration.
The manuscript has been edited as you recommended.
Line 49: “pHi” please write intracellular pH in brackets as done for Cl concentration in line 154.
The manuscript has been edited as you recommended.
Line 63: (3)??? Or line 66: (5)???
Response: We appreciate your comments. The manuscript has been edited as deletion of (3) and (5).
Line 95: “DRA”, differently from the other proteins, in this case authors has not reported the transported ions and the mechanism (see for example line 39) in this point but in a next point (line 218).
The manuscript has been edited as you recommended.
Line 113: “phosphatidylinositol 4,5-bisphosphate (PIP2)” is not a protein.
Response: We appreciate your comments. The manuscript has been edited as the word “protein” have been changed to “molecule”.
Line 131: “….]. And…”, please correct.
The manuscript has been edited as you recommended.
Line 156: “….interact with high affinity for [Cl−]i.” high affinity is towards Cl, not [Cl−]i. See also line 159.
The manuscript has been edited as you recommended.
Line 156 and 158: “concentration of [Cl−]I” is wrong, please correct with concentration of Cl−i.
The manuscript has been edited as you recommended.
Line 159 : “affinity of [Cl−]i” is “affinity for Cl-i”.
The manuscript has been edited as you recommended.
Line 165: “and various other transporters”, the previous are not transporters but organs or systems.
The manuscript has been edited as you recommended.
Line 189: legend to figure 1 contains many errors: “channels” (are transporters); “involve in” delete and substitute with “:”; [pH]i is wrong, is pHi.
The manuscript has been edited as you recommended.
Line 229, legend to figure 2: once again authors use the word “channels” speaking about transporters. Authors use both protein and gene names (AE3 and SLC26A3) without an evident meaning. Please justify the choice to use different intensity of blue for all transporters but not for one that is green. What is it the pink circle?
Response: We appreciate your comments. The manuscript has been edited as gene names to protein names. Actually, the colors didn’t have any meanings. So we just have changed the colors that mean the blue is NBC and the green is CBE. The pink circle is nucleus.
Line 254: similar problem with this legend and legend of fig 5, line 328.
The manuscript has been edited as you recommended.
Line 329: “pH level” is wrong.
The manuscript has been edited as you recommended.
Line 337-338: modify this sentence detailing.
The manuscript has been edited as you recommended.
Line 341 does not sound well.
Response: We appreciate your comments. The sentence has been deleted.
In the text is not reported a cross-reference to the table 1.
English grammar errors:
Response: We appreciate your comments. The manuscript has been edited as you recommended in all grammar errors.
line 6: “Bicarbonate transporting mechanism” is “Bicarbonate transport mechanism”
line 15: “in mechanism” is “ in the mechanism”
line 18: “its” is “their”
Line 40: “ channels are” delete “s” from channels
Line 53: “in increased” substitute in with to
Line 56: “reveled” adjust with revealed
Line 94: the sentence “have been implicated to be involved with” sounds strange, please correct
Line 97: “transporters has”…have
Line 100 “will discuss” will be discussed
Line 116-117: “….dissociates from IP3R in the stimulating state such as activation of G protein-coupled receptor and released to cytosol”, rewrite this sentence
Line 118: “…has been unknown.” Do you mean: ….has been so far unknown?
Line 124: “transporters is”, are
Line 128: “decrease”, is “decreases”
Line 133: “which act….” Is “acts”
Line 138: “…residue” is “residues”
Line 141: “signaling molecules” is singular, molecule
Line 142: “ though” do you mean through?
Line 143: “therapeutic approaches” is “therapeutic approach”
Line 146: “its” is “their”
Line 150: “ through by”, is not correct
Line 152: “In accordance with,” is not correct
Line 152: “Cl- play”, “s” missing
Line 156:” which interact”, “s” missing
Line 160: “make”, “s” missing
Line 160: “can be suggest”, delete “be”
Line 163: too much “and”
Line 186: “in cellular network” is “in the cellular network”
Line 220: “null mice results” delete “s”
Line 276: “involves in” delete in
Line 294: “slice” is “splice”
Line 299: “ in basolateral membrane” is “ in the basolateral….”
Line 303: “maintain” add “s”
Line 336: “its associated” is “their”
