ArticlebioRxiv : the preprint server for biology2024
Photo-crosslinking hERG channels causes a U.V.-driven, state-dependent disruption of kinetics and voltage dependence of activation.
Article in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors.
Funding
Abstract
Human ether-à-go-go related gene (hERG) voltage-activated potassium channels are critical for cardiac excitability. Characteristic slow closing (deactivation) in hERG is regulated by direct interaction between the N-terminal Per-Arnt-Sim (PAS) domain and the C-terminal cyclic nucleotide binding homology domain (CNBHD). We aim to understand how the PAS domain that is distal to the pore rearranges during gating to allosterically regulate the channel pore (and ion flux). To achieve this, we utilized the non-canonical amino acid 4-Benzoyl-L-phenylalanine (BZF) which is a photo-activatable cross-linkable probe, that when irradiated with ultraviolet (U.V.) light forms a double radical capable of forming covalent cross-links with C-H bond-containing groups, enabling selective and potent U.V.-driven photoinactivation of ion channel dynamics. Here we incorporate BZF directly into the hERG potassium channel PAS domain at three locations (G47, F48, and E50) using TAG codon suppression technology. hERG channels with BZF incorporated into the PAS domain (hERG-BZF) showed a significant change in the biophysical properties of the channel. hERG-G47BZF activated slowly when irradiated in the closed state (-100mV) but deactivated quickly when irradiated in both the open (0mV) and closed state. hERG-F48BZF channels showed a state independent and U.V. dose-dependent change in channel activation (slowing down) and channel deactivation (speeding up), as well as a marked change (right-shift) in the voltage-dependence of conductance. When irradiated at -100 mV hERG-E50BZF showed a state dependent and U.V. dose-dependent change in a channel activation (slowing down) and deactivation (speeding up) of channel deactivation, as well as a marked change (right-shift) in the voltage-dependence of conductance that occurred only when the channel was irradiated in the closed state (-100mV). This approach demonstrated that direct photo-crosslinking of the PAS domain in hERG channels causes a measurable change in biophysical parameters and more broadly stabilized the closed state of the channel. We propose that altered channel gating is as a direct result of reduced dynamic motions in the PAS domain of hERG due to photo-chemical crosslinking.
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.