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Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism

Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism

Authors :
Núñez Fernández, Lucía
Vaquero González, Luis Miguel
Gómez García, Ricardo
Caballero Collado, Ricardo
Mateos Cáceres, Petra
Macaya Miguel, Carlos
Iriepa Canalda, Isabel
Gálvez Ruano, Enrique
López Farre, Antonio José
Tamargo Menéndez, Juan
Delpón Mosquera, María Eva
Núñez Fernández, Lucía
Vaquero González, Luis Miguel
Gómez García, Ricardo
Caballero Collado, Ricardo
Mateos Cáceres, Petra
Macaya Miguel, Carlos
Iriepa Canalda, Isabel
Gálvez Ruano, Enrique
López Farre, Antonio José
Tamargo Menéndez, Juan
Delpón Mosquera, María Eva
Publication Year :
2024

Abstract

Objective: This study was undertaken to analyze whether nitric oxide (NO) modulates the human potassium channel hKv1.5, which generates the ultrarapid delayed rectifier current (IKur) that determines the height and duration of atrial action potentials. Methods: Currents were recorded using the whole-cell patch-clamp in Ltk- cells expressing hKv1.5 channels. Results: The NO donors (+/-)-S-Nitroso-N-acetylpenicillamine (SNAP) and sodium nitroprusside, a NO solution, and l-Arginine inhibited hKv1.5 currents in a concentration-dependent manner. The NO concentration in the cell chamber was monitored using a sensor, and the IC50 for NO-induced hKv1.5 block was 340+/-70 nM. SNAP also inhibited the IKur recorded in mouse ventricular myocytes. The NO effects were partially mediated by the activation of the soluble guanylate cyclase (sGC)/cGMP/cGMP-dependent protein kinase (PKG) pathway. The biotin-switch assay demonstrated the presence of S-nitrosylated cysteines (Cys) on the hKv1.5 protein in SNAP-treated cells. Molecular modeling of hKv1.5 channel structure suggests that S-nitrosylation of Cys331 (segment 2, S2) and Cys346 (S2) would be stabilized by hydrogen bridge bonds with Ile262 (S1) and Arg342 (S2), respectively. Conclusions: NO inhibits the hKv1.5 current by a cGMP-dependent mechanism and by the S-nitrosylation of the hKv1.5 protein, an effect that contributes to shaping the human atrial action potentials.<br />Mutua Madrileña Foundation<br />Red HERACLES<br />Depto. de Farmacología y Toxicología<br />Fac. de Medicina<br />TRUE<br />pub

Details

Database :
OAIster
Notes :
application/pdf, 1755-3245, English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1429623817
Document Type :
Electronic Resource