Preprints reviewed by eLife: An “excellent and important study” of resurgent currents in sodium channels

Read what peer reviewers thought about a recent preprint on the molecular mechanisms responsible for resurgent currents in voltage-gated sodium channels.
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eLife only reviews papers that have been posted as preprints and, when the authors agree, we post some of the outcomes of the peer-review process alongside the preprint. Authors can also post a response to this material if they wish.

This is the fourth in a series of short articles highlighting preprints that had been reviewed in this way. Links to the previous articles and more details on our peer-review process are given at the end of this article.

Preprint title: A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels

Electrical signals called “action potentials” have an important role in neurons and other “excitable” cells such as muscle cells. Action potentials are generated by transmembrane proteins called voltage-gated ion channels that can open up to allow charged ions – often sodium or calcium ions – to flow in and out of cells. In this bioRxiv preprint the authors explore the origins of a particular type of electrical signal called a resurgent current that can be generated by voltage-gated sodium channels. Many neurons require such currents in order to fire at high frequencies, and faulty resurgent currents have been implicated in pain disorders and other human diseases.

Here is what the evaluation summary for the preprint said:

This is an exciting and important study that constitutes a major advance in the molecular understanding of resurgent Na current. Reproducing resurgent current by expression of two proteins has never been done: Here, the authors have for the first time molecularly reconstituted Na channels that produce resurgent Na current. Not only do these experiments satisfactorily and convincingly address a long-standing question in the field, but they also open the door to molecular manipulation of this current, potentially of significant practical use given the proposed role of the current in several disorders and disease states, including pain. The work will be of interest to many neuroscientists.

Reviewer #3 described the results as “long-awaited” and summarized main findings of the study and its possible implications in their public review as follows:

Here, the authors have accomplished three things:

(1) They have for the first time successfully molecularly reconstituted Na channels that produce resurgent Na current by expressing the FHF4A protein with NaV1.8 or 1.9.
(2) They have also reconstituted resurgent currents by coexpressing FHF2A with NaV1.5 or 1.7.
(3) They have identified a key residue that regulates the sensitivity of NaV alpha subunits to resurgent-current mimicking open-channel block by the NaVbeta4 peptide.

Not only do these experiments satisfactorily and convincingly address a long-standing question (and give an idea of the wealth of molecular combinations that may generate resurgent current), they also open the door to molecular manipulation of this current, which will be highly informative and potentially of significant practical use, given the proposed role of the current in several disorders and disease states, including pain (as shown by these authors). The work is convincingly done and clearly presented.

Reviewer #1 was equally positive (“This is an excellent paper with extensive data and important results”), but had one concern:

It seems debatable whether the expression of Nav1.8 in ND7/23 cells constitutes truly "heterologous" expression. After all, ND7/23 cells are an immortalized DRG cell line. At the least, the authors need to explain why ND7/23 cells were used for the Nav1.8 expression and to acknowledge that ND7/23 cells may express proteins in addition to the transfected Nav1.8 and FHF that could be important for the generation of resurgent current.

The authors have posted their response to this concern alongside the preprint.

The evaluation summary, public reviews and author response were posted on April 7, 2022.

Peer review at eLife

During the eLife peer-review process our referees write ‘public reviews’ that discuss the strengths and limitations of the preprint, and our editors synthesize these into a short ‘evaluation summary’. Reviewers also produce detailed feedback for the authors, including requests for revisions and suggestions for improvement; this feedback is not posted alongside the preprint.

Links to previous articles: