Modulation of ATP-sensitive potassium channels by hydrogen sulfide and hydroxylamine
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».