Modulation of ATP-sensitive potassium channels by hydrogen sulfide and hydroxylamine
Bibliographic record
Abstract
ATP-sensitive potassium (K + ) channels (K ATP ) in vascular smooth muscle cells (VSMC) play a major role in the regulation of vascular tone by coupling cell contractility and K + fluxes to cellular metabolism.They are composed of the regulatory sulphonylurea receptors (SUR) and the pore-forming inwardly rectifying K + (Kir) channels.SUR subunits interact closely with Kir subunits by conferring their sensitivity to nucleotide or sulphonylurea.However, the modulatory mechanisms of K ATP channels in VSMC are largely unknown.In particular, the effects of hydrogen sulfide (H 2 S) and hydroxylamine (HA) on K ATP channels and underlying mechanisms have not been addressed in VSMC of resistance arteries.The combined approaches including molecular biology, biochemical assays, and patch-clamp techniques were applied.The electrophysiological and pharmacological features of native K ATP channels in VSMC and cloned K ATP channels in HEK-293 cells, and the modulation of K ATP channels by H 2 S and HA in single freshly isolated VSMC from rat mesenteric arteries were characterized.In the present study, only small conductance K ATP channels of 13 pS were found in rat mesenteric artery VSMC.The recorded macroscopic and unitary K ATP currents were activated by nucleoside diphosphate in the presence of magnesium and K + channel openers, inhibited by a specific K ATP channel blocker glibenclamide, but were insensitive to ATP inhibition.The reversal potential shifted rightward in response to the elevation of extracellular K + and matched the calculated K + equilibrium potential, indicating the basal currents in both VSMC and HEK-293 cells are carried by K + ions.Heterologous expression of Kir6.1 with SUR2B in HEK-293 cells formed functional channels and elicited whole-cell K + currents, which shared some similar biophysical iii characteristics of native K ATP channels in VSMC.Basal K ATP currents and resting membrane potential in VSMC were reduced by glibenclamide, demonstrating that K ATP channels contribute to background K + conductance and in the setting of resting membrane potential in this resistance artery.Exogenous H 2 S enhanced macroscopic and unitary K ATP currents with an EC 50 of 116 ± 8.3 µM and hyperpolarized membrane potential.H 2 S activated K ATP channels by increasing the open probability of single channels, but not single channel conductance.The reduced endogenous H 2 S production by D, L-propargylglycine resulted in the attenuation of K ATP currents.H 2 S-induced activation of K ATP channels and resultant hyperpolarization were not mediated by cGMP signaling pathway.HA enhanced reversibly K ATP currents in a dose-dependent fashion with an EC 50 of 54±3.4 µM and also hyperpolarized the cell membrane.HAstimulated K ATP currents were blocked by free radical scavengers (superoxide dismutase and N-acetyl-L-cysteine), and K ATP channels were stimulated by a free radical generating system (hypoxanthine/xanthine oxidase), indicating the involvement of superoxide (O 2 -) in HA effects.Sodium nitroprusside and 8-Br-cGMP did not affect basal K ATP currents and HA-stimulated K ATP currents, disproving the involvement of NO-sGC-cGMP-mediated signaling pathway in the HA effects.Therefore, HA-induced K ATP channel activation and hyperpolarization are likely due to the generation of O 2 -.In conclusion, K ATP channels in resistance artery VSMC serve as the regulatory targets of H 2 S and HA.These two endogenous molecule s modulate K ATP channels via different mechanisms.H 2 S may directly act on K ATP channel proteins while HA oxidized them via the formation of O 2 -, leading to the activation of K ATP channels.Thanks to Dr. Wang's inspiration and guidance, I was sculpted from barely knowing how to operate a pipette in 1997 into becoming fully capable and wholly independent in critically analyzing scientific literature, designing and executing experimental strategies, and writing, presenting, and publishing my results.Dr. Wang's commitment to work hard and strive for excellence has been a constant source of inspiration to encourage me to pursue my graduate studies.In addition, I would like to thank Dr. Wang for having the confidence in me, and allowing me to pursue my own research interests.I especially thank Dr. Wang for supporting my external studentship applications and my attendance at several scientific conferences.All in all, Dr. Wang's whole-hearted support, encouragement, and friendship in all of my endeavors was, and remains to be, invaluable to me.I would like to
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".