PKD2L1 channels segregated to the apical compartment are the exclusive dual-mode pH sensor in cerebrospinal fluid-contacting neurons
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eLife Assessment
This is an important study on the sensory roles of Cerebrospinal fluid-contacting neurons (CBF-cn) in mammals. The authors identify PKD2L1 as the predominant pH-sensing channel CBF-cn and show how the apical extension is used as an amplifier of chemical changes in the content of the Cerebrospinal fluid. The evidence is solid in experimental design but limited in mechanistic interpretation, as the electrophysiological analyses require re-evaluation.
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Abstract
Cerebrospinal fluid contacting neurons (CSFcNs) are GABAergic cells that surround the central canal (CC) of the spinal cord. Their soma is located sub-ependymally and they have a dendritic-like process that ends as a bulb (the so-called “apical process”; ApPr) inside the CC. It remains unclear how this unique anatomical organization, with the soma and the ApPr located in different extracellular environments, relates to their function as a multimodal sensor of cerebrospinal fluid (CSF) composition. One of the main physiological features of CSFcNs is a prominent spontaneous electrical activity mediated by PKD2L1 (or TRPP2) channels, a non-selective cation channel of the TRP family. PKD2L1 channels have a high single-channel conductance (around 200 pS) and can be modulated by protons and mechanical forces. In this work we investigate PKD2L1 channel sensitivity to pH and its effects on CSFcNs excitability. We demonstrate that PKD2L1 spontaneous activity generates not only phasic inward currents, but also a tonic current, both of which are modulated bidirectionally by pH with a high sensitivity around physiological values. By combining electrophysiology (direct recordings from intact and isolated ApPrs) with optical methods (laser-photolysis of protons) we further show that functional PKD2L1 channels are specifically localized in the ApPr. The spatial segregation of PKD2L1 channels, along with their biophysical properties (high single-channel conductance and pH sensitivity) and the ApPr’s unique membrane properties (very high input resistance) renders CSFcN excitability exquisitely sensitive to PKD2L1 modulation. Altogether, our findings illustrate how the ApPr’s properties are finely tuned to support its sensory role.
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eLife Assessment
This is an important study on the sensory roles of Cerebrospinal fluid-contacting neurons (CBF-cn) in mammals. The authors identify PKD2L1 as the predominant pH-sensing channel CBF-cn and show how the apical extension is used as an amplifier of chemical changes in the content of the Cerebrospinal fluid. The evidence is solid in experimental design but limited in mechanistic interpretation, as the electrophysiological analyses require re-evaluation.
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Reviewer #1 (Public review):
This study by Vitar et al. probes the molecular identity and functional specialization of pH-sensing channels in cerebrospinal fluid-contacting neurons (CSFcNs). Combining patch-clamp electrophysiology, laser-based local acidification, immunohistochemistry, and confocal imaging, the authors propose that PKD2L1 channels localized to the apical protrusion (ApPr) function as the predominant dual-mode pH sensor in these cells.
The work establishes a compelling spatial-physiological link between channel localization and chemosensory behavior. The integration of optical and electrical approaches is technically strong, and the separation of phasic and sustained response modes offers a useful conceptual advance for understanding how CSF composition is monitored.
Several aspects of data interpretation, however, …
Reviewer #1 (Public review):
This study by Vitar et al. probes the molecular identity and functional specialization of pH-sensing channels in cerebrospinal fluid-contacting neurons (CSFcNs). Combining patch-clamp electrophysiology, laser-based local acidification, immunohistochemistry, and confocal imaging, the authors propose that PKD2L1 channels localized to the apical protrusion (ApPr) function as the predominant dual-mode pH sensor in these cells.
The work establishes a compelling spatial-physiological link between channel localization and chemosensory behavior. The integration of optical and electrical approaches is technically strong, and the separation of phasic and sustained response modes offers a useful conceptual advance for understanding how CSF composition is monitored.
Several aspects of data interpretation, however, require clarification or reanalysis-most notably the single-channel analyses (event counts, Po metrics, and mixed parameters), the statistical treatment, and the interpretation of purported "OFF currents." Additional issues include PKD2L1-TRPP3 nomenclature consistency, kinetic comparison with ASICs, and the physiological relevance of the extreme acidification paradigm. Addressing these points will substantially improve reproducibility and mechanistic depth.
Overall, this is a scientifically important and technically sophisticated study that advances our understanding of CSF sensing, provided that the analytical and interpretative weaknesses are satisfactorily corrected.
(1) The authors should re-analyze electrophysiological data, focusing on macroscopic currents rather than statistically unreliable Po calculations. Remove or revise the Po analysis, which currently conflates current amplitude and open probability.
(2) PKD2L1-TRPP3 nomenclature should be clarified and all figure labels, legends, and text should use consistent terminology throughout.
(3) The authors should reinterpret the so-called OFF currents as pH-dependent recovery or relaxation phenomena, not as distinct current species. Remove the term "OFF response" from the manuscript.
(4) Evidence for physiological relevance should be provided, including data from milder acidification (pH 6.5-6.8) and, where appropriate, comparisons with ASIC-mediated currents to place PKD2L1 activity in context.
(5) Terminology and data presentation should be unified, adopting consistent use of "predominant" (instead of "exclusive") and "sustained" (instead of "tonic"), and all statistical formats and units should be standardized.
(6) The Discussion should be expanded to address potential Ca²⁺-dependent signaling mechanisms downstream of PKD2L1 activation and their possible roles in CSF flow regulation and central chemoreception.
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Reviewer #2 (Public review):
Summary:
Cerebrospinal fluid contacting neurons (CSF-cNs) are GABAergic cells surrounding the spinal cord central canal (CC). In mammals, their soma lies sub-ependymally, with a dendritic-like apical extension (AP) terminating as a bulb inside the CC.
How this anatomy-soma and AP in distinct extracellular environments relate to their multimodal CSF-sensing function remains unclear.
The authors confirm that in GATA3:GFP mice, where these cells are labeled, that CSFcNs exhibit prominent spontaneous electrical activity mediated by PKD2L1 (TRPP2) channels, non-selective cation channels with ~200 pS conductance modulated by protons and mechanical forces.
They investigated PKD2L1 pH sensitivity and its effects on CSFcN excitability. They uncovered that PKD2L1 generates both phasic and tonic currents, …
Reviewer #2 (Public review):
Summary:
Cerebrospinal fluid contacting neurons (CSF-cNs) are GABAergic cells surrounding the spinal cord central canal (CC). In mammals, their soma lies sub-ependymally, with a dendritic-like apical extension (AP) terminating as a bulb inside the CC.
How this anatomy-soma and AP in distinct extracellular environments relate to their multimodal CSF-sensing function remains unclear.
The authors confirm that in GATA3:GFP mice, where these cells are labeled, that CSFcNs exhibit prominent spontaneous electrical activity mediated by PKD2L1 (TRPP2) channels, non-selective cation channels with ~200 pS conductance modulated by protons and mechanical forces.
They investigated PKD2L1 pH sensitivity and its effects on CSFcN excitability. They uncovered that PKD2L1 generates both phasic and tonic currents, bidirectionally modulated by pH with high sensitivity near physiological values.
Combining electrophysiology (intact and isolated AP recordings) with elegant laser-photolysis, they show that functional PKD2L1 channels localize specifically to the apical extension (AP).
This spatial segregation, coupled with PKD2L1's biophysical properties (high conductance, pH sensitivity) and the AP's unique features (very high input resistance), renders CSFcN excitability highly sensitive to PKD2L1 modulation. Their findings reveal how the AP's properties are optimised for its sensory role.
Strengths:
This is a very convincing demonstration using elegant and challenging approaches (uncaging, outside out patch of the AP) together to form a complete understanding of how these sensory cells can detect the changes of pH in the CSF so finely.
Weaknesses:
The following do not constitute weaknesses; rather, they are minor requests that this reviewer considers would complete this beautiful study.
(1) It would be nice to quantify further the relation in spontaneous as well as in acidic or basic pH between the effects observed on channel opening and holding current: do they always vary together and in a linear way?
(2) Since CSF-cNs also respond to changes in osmolarity (Orts Dell Immagine 2013) & mechanosensory stimulations in a PKD2L1 dependent manner (Sternberg NC 2018), it would be nice to test the same results whether the same results hold true on the role of PKD2L1 in AP for pressure application of changes in osmolarity.
In mice, like in fish (Sternberg et al, NC 2018), we can observe throughout the figures that a large fraction of the channel activity occurs with partial and very fast openings of the PKD2L1 channel. I recommend the authors analyse the points below:
a) To what extent do these partial openings of the channel contribute to the changes in holding current and resting potential?
b) In the trace from the outside out AP, it looks like the partial transient openings are gone. Can the authors verify whether these partial openings are only present in somatic recordings?(3) Previous studies have observed expression of metabotropic Glutamate receptors in CSF-cNs (transcriptome from Prendergast et al CB 2023). The authors only used blockers for ionotropic glutamate receptors in their recordings: could it be that these metabotropic receptors influence the response to uncaging of MNI-Glu when glutamate is co-released with a proton?
(4) In the outside out patch of the AP, PKD2L1 unitary currents appear rare. Could it be that the disruption in the cilium or underlying actin/myosin cytoskeleton drastically alter the open probability of the channel?
(5) Could the authors use drugs against ASIC to specify which ASIC channels contribute to the pH response in the soma?
(6) This is out of the scope of this study, but we did observe in fish a very rarely-opening channel in the PKD2L1KO mutant. I wonder if the authors have similar observations in the conditions where PKD2L1 is mainly in the closed state.
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Author response:
Public Reviews:
Reviewer #1 (Public review):
This study by Vitar et al. probes the molecular identity and functional specialization of pH-sensing channels in cerebrospinal fluid-contacting neurons (CSFcNs). Combining patch-clamp electrophysiology, laser-based local acidification, immunohistochemistry, and confocal imaging, the authors propose that PKD2L1 channels localized to the apical protrusion (ApPr) function as the predominant dual-mode pH sensor in these cells.
The work establishes a compelling spatial-physiological link between channel localization and chemosensory behavior. The integration of optical and electrical approaches is technically strong, and the separation of phasic and sustained response modes offers a useful conceptual advance for understanding how CSF composition is monitored.
Several aspects of …
Author response:
Public Reviews:
Reviewer #1 (Public review):
This study by Vitar et al. probes the molecular identity and functional specialization of pH-sensing channels in cerebrospinal fluid-contacting neurons (CSFcNs). Combining patch-clamp electrophysiology, laser-based local acidification, immunohistochemistry, and confocal imaging, the authors propose that PKD2L1 channels localized to the apical protrusion (ApPr) function as the predominant dual-mode pH sensor in these cells.
The work establishes a compelling spatial-physiological link between channel localization and chemosensory behavior. The integration of optical and electrical approaches is technically strong, and the separation of phasic and sustained response modes offers a useful conceptual advance for understanding how CSF composition is monitored.
Several aspects of data interpretation, however, require clarification or reanalysis-most notably the single-channel analyses (event counts, Po metrics, and mixed parameters), the statistical treatment, and the interpretation of purported "OFF currents." Additional issues include PKD2L1-TRPP3 nomenclature consistency, kinetic comparison with ASICs, and the physiological relevance of the extreme acidification paradigm. Addressing these points will substantially improve reproducibility and mechanistic depth.
Overall, this is a scientifically important and technically sophisticated study that advances our understanding of CSF sensing, provided that the analytical and interpretative weaknesses are satisfactorily corrected.
(1) The authors should re-analyze electrophysiological data, focusing on macroscopic currents rather than statistically unreliable Po calculations. Remove or revise the Po analysis, which currently conflates current amplitude and open probability.
We agree with the reviewer that the Po analysis has strong limitations, particularly in experiments where the recording times are short, such as when extracellular pH is changed via photolysis (Figure 4D) or puff application (Figure 3Aa). To circumvent this problem and not rely solely on Po estimations, we used alternative methods, including an analysis of the total membrane charge (extensively used throughout the manuscript, as in Figures 3A and 4D) and an analysis of event latencies (Figure 4G). Nevertheless, single channel recordings contain information that is not included in the macroscopic current analysis. In the revised version, we intend to stress that the elementary current amplitude is conserved during manipulations such as pH changes, leaving the total number of channels (N) and the channel open probability (Po) as possible culprits for the current changes. Since these changes are rapid and reversible, it is likely that N remains constant while Po changes. To address the reviewer’s concern, we propose the following changes/reanalysis: (i) report in each condition the minimum N (based on the maximum number of simultaneously open channels; for example, in Figure 3Aa, the minimum N goes from 4-5 in control conditions to 1 during the puff of the pH 6.4 solution). Although imperfect, this method provides a tentative estimate of Po; (ii) report the fraction of time that the channels remain open; (iii) revise the text and figures to use the expression “apparent Po” instead of “Po”, acknowledging the limitations of the measurement in short recordings. We also acknowledge that some traces (Figure 3Aa, top) may appear confusing, as they seem to show macroscopic currents. We will modify these figures by including the amplitude histograms (as in Figure 1Bb) to clearly demonstrate that recordings from CSFcNs primarily reflect single-channel activity when challenged with pH changes.
(2) PKD2L1-TRPP3 nomenclature should be clarified and all figure labels, legends, and text should use consistent terminology throughout.
We agree with the reviewer that the nomenclature for the polycystin protein family is confusing. In this manuscript, we have followed the nomenclature proposed in a recent comprehensive review on polycystin channels by Palomero, Larmore and DeCaen (Palomero et al. 2023), which refer to the channels by their gene names. As indicated in that review, the PKD2L1 channel corresponds to TRPP2 (previously known as TRPP3, see their Table 1). However, in another recent review on TRP channels, the PKD2L1 channel is referred to as TRPP3 (Zhang et al. 2023). To prevent any ambiguity, we will remove references to the TRPP nomenclature from the text and exclusively use the PKD2L1 acronym.
(3) The authors should reinterpret the so-called OFF currents as pH-dependent recovery or relaxation phenomena, not as distinct current species. Remove the term "OFF response" from the manuscript.
Although largely used in the literature, we concur with the reviewer that the term “OFF response” is not very helpful from a biophysical perspective as it may imply the existence of a distinct current. Consequently, we will remove the terms “OFF response” and “OFF current” from the revised manuscript and replace them with the term “photolysis-evoked PKD2L1 current”. Furthermore, to improve the logical flow, we will condense the two sections (“The proton-induced current is an off-current” and “The off-current is mediated by the activation of PKD2L1 channels”) into a single, new section titled “The photolysis-induced current is mediated by PKD2L1 channels”. This consolidation will prevent the artificial separation of the description of this current. Finally, we will revise the discussion to better characterize this photolysis-evoked phenomenon as a recovery current.
(4) Evidence for physiological relevance should be provided, including data from milder acidification (pH 6.5-6.8) and, where appropriate, comparisons with ASIC-mediated currents to place PKD2L1 activity in context.
This point is partly addressed in Figure 3. The data indicate that PKD2L1 channels are highly sensitive to pH variations within the physiological range. To strengthen this conclusion, we will add the EC50 values derived from the curve fittings to the figure. Regarding ASIC-mediated currents, one of our main conclusions is that ASICs are not present in the apical process (ApPr), as the effects of proton photolysis in the ApPr are not blocked by ASIC antagonists. Our results suggest that PKD2L1 channels are the exclusive pH sensitive channels in the ApPr. ASIC channels likely mediate acid sensitivity in the soma, although we have not investigated the latter in detail. We intend to modify the Discussion in order to provide a physiological framework linking channel activity with physiological and pathophysiological pH changes.
(5) Terminology and data presentation should be unified, adopting consistent use of "predominant" (instead of "exclusive") and "sustained" (instead of "tonic"), and all statistical formats and units should be standardized.
Folllowing the reviewer’s suggestions, an exhaustive rephrasing will be performed to unify terminology, data presentation and correct the text.
(6) The Discussion should be expanded to address potential Ca²⁺-dependent signaling mechanisms downstream of PKD2L1 activation and their possible roles in CSF flow regulation and central chemoreception.
This is indeed a very interesting and currently unresolved point in the physiology of CSFcNs. Published data indicate that calcium influx through PKD2L1 channels is a key regulator of apical process (ApPr) physiology. These channels are calcium permeable yet are also inhibited by intracellular calcium (DeCaen et al. 2016). Additionally, ultrastructural data show that the ApPr is rich in mitochondria and tubulo-vesicular structures resembling the Golgi apparatus (Bruni et Reddy 1987; Bjugn et al. 1988; Nakamura et al. 2023), intracellular organelles critical for calcium homeostasis. Altogether, this evidence suggests that intra-ApPr calcium concentration must be finely regulated, both in space and time, for the ApPr to fulfill its physiological roles. Based on the existing literature, we can speculate that these calcium signals are decoded by several systems: (i) calcium may act as a second messenger, linking the activation of the multimodal PKD2L1 channels to changes in CSFcN excitability, which in turn regulates spinal neuronal networks controlling locomotor activity; (ii) calcium could initiate the neurosecretion of various molecules from the ApPr into the central canal, as proposed by the Wyart group in the zebrafish in the context of bacterial infections (Prendergast et al. 2023); (iii) calcium could activate the Hedgehog signaling pathway (as has been shown by Delling et al. 2013); iv) calcium could modulate CSF flow by modulating ependymal cells ciliary activity. Resolving these downstream pathways is essential to fully define the role of CSFcNs as integrators of cerebrospinal fluid homeostasis. We will expand on this topic in the Discussion section of the revised ms.
Reviewer #2 (Public review):
Summary:
Cerebrospinal fluid contacting neurons (CSF-cNs) are GABAergic cells surrounding the spinal cord central canal (CC). In mammals, their soma lies sub-ependymally, with a dendritic-like apical extension (AP) terminating as a bulb inside the CC.
How this anatomy-soma and AP in distinct extracellular environments relate to their multimodal CSF-sensing function remains unclear.
The authors confirm that in GATA3:GFP mice, where these cells are labeled, that CSFcNs exhibit prominent spontaneous electrical activity mediated by PKD2L1 (TRPP2) channels, non-selective cation channels with ~200 pS conductance modulated by protons and mechanical forces.
They investigated PKD2L1 pH sensitivity and its effects on CSFcN excitability. They uncovered that PKD2L1 generates both phasic and tonic currents, bidirectionally modulated by pH with high sensitivity near physiological values.
Combining electrophysiology (intact and isolated AP recordings) with elegant laser-photolysis, they show that functional PKD2L1 channels localize specifically to the apical extension (AP).
This spatial segregation, coupled with PKD2L1's biophysical properties (high conductance, pH sensitivity) and the AP's unique features (very high input resistance), renders CSFcN excitability highly sensitive to PKD2L1 modulation. Their findings reveal how the AP's properties are optimised for its sensory role.
Strengths:
This is a very convincing demonstration using elegant and challenging approaches (uncaging, outside out patch of the AP) together to form a complete understanding of how these sensory cells can detect the changes of pH in the CSF so finely.
Weaknesses:
The following do not constitute weaknesses; rather, they are minor requests that this reviewer considers would complete this beautiful study.
(1) It would be nice to quantify further the relation in spontaneous as well as in acidic or basic pH between the effects observed on channel opening and holding current: do they always vary together and in a linear way?
Following the reviewer’s suggestion, we performed a Spearman’s rank correlation test. The analysis revealed a significant correlation between the changes in the apparent open probability and the holding current in paired experiments (control vs pH 6.4 pressure applications; p < 0.05, Spearman r = 0.72 and critical value = 0.67). The Pearson correlation coefficient calculated on the same data set was r = 0.63 (critical value = 0.632), indicating that the correlation is not linear. We thank the reviewer for raising this point and will add this analysis to the manuscript.
(2) Since CSF-cNs also respond to changes in osmolarity (Orts Dell Immagine 2013) & mechanosensory stimulations in a PKD2L1 dependent manner (Sternberg NC 2018), it would be nice to test the same results whether the same results hold true on the role of PKD2L1 in AP for pressure application of changes in osmolarity.
This is a very important point. As the reviewer notes, previous experimental evidence indicates that CSFcNs are also sensitive to osmolarity changes and mechanical stimulation in a PKD2L1-dependent manner. It is therefore reasonable to assume that, similar to pH sensitivity, osmotic and mechanical sensitivity depend on channels localized to the apical process (ApPr). Regarding mechanosensitivity, this spatial segregation could be tested by mechanically stimulating either the ApPr or the soma with a piezo-controlled blunt pipette (see, for example, Hao et al. 2013). Assessing sensitivity to osmotic changes, however, is more challenging, as pressure application lacks the spatial resolution to discriminate between compartments in such a compact cell. In theory, a highly localized osmotic jump could be achieved via photolysis, provided a caged compound that releases many osmotic particles simultaneously is used. In typical photolysis experiments, a localized osmotic change is produced, but its amplitude is very low (on the order of 1 to 2 mOsm).
In mice, like in fish (Sternberg et al, NC 2018), we can observe throughout the figures that a large fraction of the channel activity occurs with partial and very fast openings of the PKD2L1 channel. I recommend the authors analyse the points below:
(a) To what extent do these partial openings of the channel contribute to the changes in holding current and resting potential?
As the reviewer indicates, these partial and rapid openings are characteristic of PKD2L1 single-channel activity and appear to be conserved across species. However, estimating their precise contribution to the sustained current would require a detailed channel model, which is currently lacking. Indeed, the exact mechanism underlying this prominent sustained current in CSFcNs remains unknown and should definitely be addressed in future work.
(b) In the trace from the outside out AP, it looks like the partial transient openings are gone. Can the authors verify whether these partial openings are only present in somatic recordings?
The outside-out recordings from the apical process also show some partial openings (see the upper trace in Figure 4Db). We will specifically mention this important point in the revised version of the ms.
(3) Previous studies have observed expression of metabotropic Glutamate receptors in CSF-cNs (transcriptome from Prendergast et al CB 2023). The authors only used blockers for ionotropic glutamate receptors in their recordings: could it be that these metabotropic receptors influence the response to uncaging of MNI-Glu when glutamate is co-released with a proton?
We thank the reviewer for pointing out the presence of metabotropic glutamate receptors in CSFcNs. However, our evidence indicates that metabotropic receptors do not contribute to the response when uncaging MNI-glutamate. This conclusion is supported by two observations: (i) the response obtained when uncaging MNI-γLGG, which does not release glutamate (Figure 5Ab), and (ii) the response obtained when uncaging protons from DPNI-GABA (data not shown) (DPNI-GABA is a GABA cage with photochemistry similar to MNI cages that also releases a proton upon photolysis; Trigo et al. 2009), are the same. In both experiments (uncaging MNI-γLGG or DPNI-GABA) a clear photolysis-evoked PKD2L1 current is observed.
(4) In the outside out patch of the AP, PKD2L1 unitary currents appear rare. Could it be that the disruption in the cilium or underlying actin/myosin cytoskeleton drastically alter the open probability of the channel?
The reviewer is correct in noting that the opening frequency of PKD2L1 channels appears lower in outside-out patches than in whole-ApPr recordings, although we have not quantified this. We interpreted this difference as reflecting a lower channel number. However, as the reviewer suggests, a plausible alternative explanation is that the channel's biophysical properties are altered when removed from its native ionic environment or when it loses interactions with regulatory proteins. We will address this point in the Discussion.
(5) Could the authors use drugs against ASIC to specify which ASIC channels contribute to the pH response in the soma?
As described in the manuscript, we performed experiments with ASIC antagonists, although we did not attempt to characterize the specific ASIC subtype mediating the somatic response. Based on the published literature, we used both psalmotoxin-1, which blocks ASIC1 channels, and APETx2, which blocks ASIC3 channels. The presence of ASIC1 in mouse CSFcNs has been demonstrated previously (Orts-Del’immagine et al. 2012; Orts-Del’Immagine et al. 2016), while ASIC3 has been identified in lamprey CSFcNs (Jalalvand et al. 2016). When applying an acidic solution to the soma, we recorded an inward current that was substantially blocked by psalmotoxin-1, although a small residual component persisted, consistent with the earlier findings of Orts-Del’Immagine et al. We did not attempt to block this remaining Psalmotoxin1‑insensitive component.
(6) This is out of the scope of this study, but we did observe in fish a very rarely-opening channel in the PKD2L1KO mutant. I wonder if the authors have similar observations in the conditions where PKD2L1 is mainly in the closed state.
We have never seen such kind of openings in our recordings (when the channel is closed or in the presence of dibucaine).
References
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