Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article is very well presented, from the general to the particular relevance of the different isoforms of potassium channels with two-pore domain (K2P), highlighting their activity, structural composition and their involvement in different pathologies. The table and figures clearly summarize what is in the text. I only have two comments as follows:

K2P or K₂P abbreviations should be only one…I suggest choosing one along the text.

I suggest giving an explanation about the order of the coded genes, this would be better for the reader ----For example, KCNK7 encodes for TWIK-1, KCNK6 for TWIK-2 and KCNK7 for K2P7.1 (different name) and so on.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

• Dear Authors,
  Your review addresses an important and emerging field, and the manuscript contains strong mechanistic explanations and clinically relevant discussion, especially in the sections on TASK-1 and pulmonary arterial hypertension. The work is promising and has clear potential for publication. However, substantial revision is required to improve clarity, consistency, formatting, and critical depth. Addressing contradictory findings, refining the scope, correcting errors, and strengthening references will significantly enhance the quality of the review. With these major revisions, the manuscript could become a valuable contribution to the field.

• Line 11–14: The correspondence line is repetitive (“ADDRESS FOR CORRESPONDENCE”). Please simplify formatting according to journal style.

• Line 15–20: Word count and character count information is incomplete and should be removed from the manuscript body unless required in a separate submission form.

• Line 23–48 (Abstract): The abstract is informative but too long and contains excessive mechanistic detail. Please shorten and focus on the main scope, key findings, and clinical relevance.

• Line 37–43: Statements about mutations and therapeutic activators need stronger referencing and clearer distinction between human evidence vs. animal/preclinical studies.

• Line 49–52: Graphical abstract is mentioned but not properly inserted in the formatted manuscript. Ensure compliance with Pharmaceuticals journal graphical abstract requirements.

• Line 54–60: The introduction is clear but would benefit from adding a brief explanation of why K2P channels are emerging therapeutic targets compared to classical potassium channels.

• Line 61–66: The term “time-independent” is used; please clarify with electrophysiological context and cite appropriate primary literature.

• Line 69–71: Rectification differences across subfamilies are briefly stated but require more explanation or a supporting figure/table.

• Line 72–73: Section heading grammar should be corrected (“K2P Channel Subfamilies”).

• Line 75–89: TWIK subfamily description is informative, but the physiological relevance to cardiovascular/pulmonary systems is not emphasized enough.

• Line 86–88: The statement that KCNK7 is “functionally silent” should be supported by more recent references or discussed cautiously.

• Line 90–103: TREK subfamily section contains many neurological details (depression, nociception). Consider shortening or linking more directly to cardiopulmonary relevance.

• Line 104–120: TASK subfamily section is strong but includes overly long explanation of the GHK equation. This could be reduced or moved to supplementary explanation.

• Line 121–129: TALK channels are described as having limited cardiovascular relevance; therefore, the section could be condensed.

• Line 130–141: THIK and TRESK sections are brief but need clearer justification for inclusion in this cardiovascular-focused review.

• Line 142–150: Excellent mechanistic explanation of membrane stabilization in PASMCs; however, please add more transitional wording connecting pulmonary and cardiac roles.

• Line 154–158: The role in cardiac action potential is mentioned briefly; this section could be expanded with more electrophysiological evidence.

• Line 161–173: Figure-1 is referenced but formatting should be corrected (“Figure 1” not “Figure-1”).

• Line 186–205: Table 1 is useful but should include references for each disease association listed.

• Line 194–204: TASK-1 expression changes in AF are contradictory across studies. Authors should clearly explain differences between chronic AF, perioperative AF, and HF-associated AF.

• Line 207–221: TASK-1 deletion effects are interesting, but the discussion should clarify whether inhibition is beneficial or risky depending on disease context.

• Line 222–228: Contradictory findings on TWIK-1 regulation in AF require deeper critical discussion rather than listing opposing results.

• Line 229–245: TREK-1 role in ventricular myocardium is well presented, but more emphasis on clinical translation is needed.

• Line 253–270: Pulmonary vascular section is strong but somewhat repetitive with earlier mechanistic descriptions.

• Line 271–297: TREK-1 hyperoxia discussion contains an error: Line 276 refers to TASK-1 instead of TREK-1. Please correct.

• Line 298–320: Influenza A lung injury section is interesting but may be too detailed for the scope of a vascular review. Consider shortening.

• Line 321–339: Pulmonary hypertension definitions are correct but should cite updated ESC/ERS guidelines (2022).

• Line 340–373: TASK-1 in PAH is very well described and represents one of the strongest parts of the manuscript.

• Line 374–401: TWIK-2 knockout studies are relevant, but the review should address limitations of murine models for human PAH translation.

• Line 402–442: GPCR signaling section is important; however, some citations are incorrectly formatted (e.g., “[59, [67], [68]”). Please revise reference formatting.

• Line 418–421: The mechanistic link between ET-1 signaling and vascular remodeling is well explained but would benefit from a summary schematic.

• Line 457 onward: The heading “Role of K2P Channels in Systemic Hypertension…” appears without numbering. Please ensure consistent section numbering.

• Line 479–517: Conclusions and clinical implications are strong but should include clearer future directions and mention current limitations in drug development.

• References section: Several references appear incomplete or poorly formatted, with broken titles and inconsistent DOI placement. Major reference editing is required.

• Overall language: The manuscript is generally readable but requires grammatical polishing, especially for article consistency (“a” vs “the”), hyphenation, and tense.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript from Abdelnasser et al. is a review dealing with role of K₂P channels in cardiovascular and pulmonary vascular physiology and disease, then proposing them as key targets to treat those diseases.

The manuscript is interesting and well structured, covering key findings on the topic. It is organized introducing the general characteristics of the different K₂P subfamilies, and then explaining the physiological functions of these channels in cardiovascular and pulmonary vasculature, as well as their role in the diseases associated to these systems. In general, the manuscript is ready to be published although I suggest some minor changes to consider.

 

• Line 70 and 80. In line 70 you mention that TWIK-1 exhibits inward rectification but in line 80 you mention that “possibly” display inward rectification. Please, clarify this point.
• Line 143, PASMC should be defined since it is the first time it is mentioned.
• In figure 1, in the physiological condition box, the figure with the channel in the membrane does not contribute anything. In the box in the middle, K2P should be K₂ Once again, it is unclear what purpose the channel in the membrane serves. Finally in the right box, the sentences starting with the black circle are not aligned. In addition, for pulmonary arterial hypertension, a subsection is created with the characteristics of the process, but not for the previous three (atrial fibrillation, cardiac hypertrophy, and heart failure).
• In Table 1, in the last four entries, the associated diseases are not mentioned in the middle column; the same is true in the right column, where the function or pathophysiological mechanism is not added. Perhaps those entries should be deleted. Also, in the left column header, K2P should be K₂
• In line 366, I suggest to change “and” for “while”.
• The section ”Role of K2P Channels in Systemic Hypertension and Vascular Pathology” should be section 6. As it stands now, it appears to be a subsection of section 5, but it has nothing to do with GPCRs.
• Line 500, add an space before [76].

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript gives a concise overview on the field of K2P potassium channels. Following basic information on the structure and groups of the channels, their role in cardiac disease, pulmonary hypertension and systemic hypertension is discussed. The choice of topic is excellent. The manuscript does not contain a methodological description how the included papers were chosen. No risk of bias assessment was performed. English language needs minimal correction. The review is overall a valuable and informative work.

 

Table 1 might include the respective references.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf