Activation of neurokinin-III receptors modulates human atrial TASK-1 currents

• Verfasst von: Wiedmann, Felix Tobias [VerfasserIn]
• Verfasst von: Paasche, Amelie [VerfasserIn]
• Verfasst von: Nietfeld, Jendrik [VerfasserIn]
• Verfasst von: Kraft, Manuel [VerfasserIn]
• Verfasst von: Meyer, Anna L. [VerfasserIn]
• Verfasst von: Warnecke, Gregor [VerfasserIn]
• Verfasst von: Karck, Matthias [VerfasserIn]
• Verfasst von: Frey, Norbert [VerfasserIn]
• Verfasst von: Schmidt, Constanze [VerfasserIn]
• Titel: Activation of neurokinin-III receptors modulates human atrial TASK-1 currents
• Verf.angabe: Felix Wiedmann, Amelie Paasche, Jendrik Nietfeld, Manuel Kraft, Anna L. Meyer, Gregor Warnecke, Matthias Karck, Norbert Frey, Constanze Schmidt
• E-Jahr: 2023
• Jahr: November 2023
• Umfang: 11 S.
• Fussnoten: Gesehen am 17.01.2024
• Titel Quelle: Enthalten in: Journal of molecular and cellular cardiology
• Ort Quelle: New York, NY [u.a.] : Elsevier, 1970
• Jahr Quelle: 2023
• Band/Heft Quelle: 184(2023), Seite 26-36
• ISSN Quelle: 1095-8584
• DOI: doi:10.1016/j.yjmcc.2023.09.010
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Arrhythmia
• Sach-SW: Atrial fibrillation
• Sach-SW: Neurokinin-III receptor
• Sach-SW: Neuropeptides
• Sach-SW: TASK-1
• K10plus-PPN: 1878347411

Abstract

Rationale - The neurokinin-III receptor was recently shown to regulate atrial cardiomyocyte excitability by inhibiting atrial background potassium currents. TASK-1 (hK2P3.1) two-pore-domain potassium channels, which are expressed atrial-specifically in the human heart, contribute significantly to atrial background potassium currents. As TASK-1 channels are regulated by a variety of intracellular signalling cascades, they represent a promising candidate for mediating the electrophysiological effects of the Gq-coupled neurokinin-III receptor. - Objective - To investigate whether TASK-1 channels mediate the neurokinin-III receptor activation induced effects on atrial electrophysiology. - Methods and results - In Xenopus laevis oocytes, heterologously expressing neurokinin-III receptor and TASK-1, administration of the endogenous neurokinin-III receptor ligands substance P or neurokinin B resulted in a strong TASK-1 current inhibition. This could be reproduced by application of the high affinity neurokinin-III receptor agonist senktide. Moreover, preincubation with the neurokinin-III receptor antagonist osanetant blunted the effect of senktide. Mutagenesis studies employing TASK-1 channel constructs which lack either protein kinase C (PKC) phosphorylation sites or the domain which is regulating the diacyl glycerol (DAG) sensitivity domain of TASK-1 revealed a protein kinase C independent mechanism of TASK-1 current inhibition: upon neurokinin-III receptor activation TASK-1 channels are blocked in a DAG-dependent fashion. Finally, effects of senktide on atrial TASK-1 currents could be reproduced in patch-clamp measurements, performed on isolated human atrial cardiomyocytes. - Conclusions - Heterologously expressed human TASK-1 channels are inhibited by neurokinin-III receptor activation in a DAG dependent fashion. Patch-clamp measurements, performed on human atrial cardiomyocytes suggest that the atrial-specific effects of neurokinin-III receptor activation on cardiac excitability are predominantly mediated via TASK-1 currents.