Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

Neuropeptides as novel regulators of human atrial TASK-1 potassium currents

F. Wiedmann1, J. Nietfeld1, A. Paasche1, M. Kraft1, R. Arif2, J. Kremer2, G. Warnecke2, M. Karck2, N. Frey1, C. Schmidt1

1Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; 2Klinik für Herzchirurgie, Universitätsklinikum Heidelberg, Heidelberg;

Background/Introduction: The neurokinin-III receptor (NK3R) was recently shown to regulate action potential duration (APD) in atrial cardiomyocytes by inhibition of a background potassium current. In the human heart, TASK-1 (hK2P3.1) two-pore-domain potassium channels display atrial-specific expression. Because of their phospholipase C (PLC)-dependent regulation, TASK-1 channels are a promising candidate to mediate APD prolongation via the Gq-coupled neurokinin-III receptor. Purpose: To investigate whether TASK-1 channels mediate NK3R activation-induced APD prolongation and to dissect the underlying molecular mechanisms. Methods: Patch-clamp measurements were performed in atrial cardiomyocytes isolated from patients with sinus rhythm and atrial fibrillation. Xenopus laevis oocytes heterologously expressing hTASK-1 and hNK3R were subjected to two-electrode voltage-clamp recordings. Results: In Xenopus oocytes heterologously overexpressing hNK3R and hTASK-1 administration of substance P or neurokinin B resulted in 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. Pharmacological experiments and mutagenesis studies could show a protein kinase C (PKC)-independent mechanism of TASK-1 current inhibition: upon NK3R activation TASK-1 channels are blocked via Gq-mediated PLC activation, in a DAG-dependent fashion. Finally, effects of senktide on atrial background currents could be reproduced in human atrial cardiomyocytes isolated from patients with atrial fibrillation. Conclusion: Neurokinin-III receptor stimulation suppresses background potassium currents in isolated human atrial cardiomyocytes from patients with atrial fibrillation. Heterologously expressed human TASK-1 channels are inhibited by neurokinin-III receptor activation in a PLC and DAG dependent fashion, suggesting neuropeptides as novel regulators of human atrial TASK-1 currents.

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