Regulation of transient Na<sup>+</sup> conductance by intra‐ and extracellular K<sup>+</sup> in the human delayed rectifier K<sup>+</sup> channel Kv1.5
Notice bibliographique
Résumé
1. Significant Na+ conductance has been described in only a few native and cloned K+ channels, but has been used to characterize inactivation and K+ binding within the permeation pathway, and to refine models of K+ flux through multi-ion pores. Here we use Na+ permeation of the delayed rectifier K+ channel Kv1.5 to study extra- and intracellular K+ (K+o and K+i, respectively) regulation of conductance and inactivation, using whole-cell recording from human embryonic kidney (HEK)-293 cells. 2. Kv1.5 Na+ currents in the absence of K+o and K+i were confirmed by: (i) resistance of outward Na+ currents to dialysis by K+-free solutions; (ii) tail current reversal potential changes with Na+o with a slope of 55.8 mV per decade; (iii) block by 4-aminopyridine (50 % at 50 microM), and resistance to Cl- channel inhibition. 3. Na+ currents were transient followed by a small sustained current. An envelope test confirmed that activated Kv1.5 channels conducted Na+, and that rapid current decay reflected C-type inactivation. Sustained currents ( approximately 13 % of peak) represented Na+ flux through inactivated Kv1.5 channels. 4. K+o could modulate the maximum available Na+ conductance in the stable cell line while channels were closed. Before the first pulse of a train, increasing K+o concentration increased the subsequent Na+ conductance from approximately 15 (0 mM K+o) to 30 nS (5 mM K+o), with a Kd of 23 microM. Repeated low rate depolarizations in Na+i/Na+o solutions induced a use-dependent loss of Kv1.5 channel Na+ conductance, distinct from that caused by C-type inactivation. K+o binding that sensed little of the electric field could prevent this secondary loss of available Kv1.5 channels with a Kd of 230 microM. These two effects on conductance were both voltage independent, and had no effect on channel inactivation rate. 5. K+o concentrations >= 0.3 mM slowed the inactivation rate in a strongly voltage-dependent manner. This suggested it could compete for binding at a K+ site or sites deeper in the pore, as well as restoring the Na+ conductance. K+i was able to modulate the inactivation rate but was unable to affect conductance. 6. Mutation of arginine 487 in the outer pore region of the channel to valine (R487V) greatly reduced C-type inactivation in Na+ solutions, caused loss of channel use dependence, and prevented any conductance increase upon the addition of 0.1 mM K+o. Our results confirm the existence of a high affinity binding site at the selectivity filter that regulates inactivation, and also reveals the presence of at least one additional high affinity outer mouth site that predominantly regulates conductance of resting channels, and protects channels activated by depolarization when they conduct Na+.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 tête enseignante, 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 ».