Activation of neurokinin-III receptors modulates human atrial TASK-1 currents.
J Mol Cell Cardiol
; 184: 26-36, 2023 11.
Article
em En
| MEDLINE
| ID: mdl-37793594
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 ANDRESULTS:
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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fibrilação Atrial
/
Canais de Potássio de Domínios Poros em Tandem
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Mol Cell Cardiol
Ano de publicação:
2023
Tipo de documento:
Article