Gi/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN

eLife

Fabian Philippart¹  Zayd M Khaliq¹ 

[1] Cellular Neurophysiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Maryland, United States;

关键词: dopamine neurons;    sodium leak channel;    Gi/o protein-coupled receptor;    GABA-B receptors;    D2 receptors;    substantia nigra;   

DOI  :  10.7554/eLife.40984

来源: DOAJ

【 摘 要 】

Dopamine (D2) receptors provide autoinhibitory feedback onto dopamine neurons through well-known interactions with voltage-gated calcium channels and G protein-coupled inwardly-rectifying potassium (GIRK) channels. Here, we reveal a third major effector involved in D2R modulation of dopaminergic neurons - the sodium leak channel, NALCN. We found that activation of D2 receptors robustly inhibits isolated sodium leak currents in wild-type mice but not in NALCN conditional knockout mice. Intracellular GDP-βS abolished the inhibition, indicating a G protein-dependent signaling mechanism. The application of dopamine reliably slowed pacemaking even when GIRK channels were pharmacologically blocked. Furthermore, while spontaneous activity was observed in nearly all dopaminergic neurons in wild-type mice, neurons from NALCN knockouts were mainly silent. Both observations demonstrate the critical importance of NALCN for pacemaking in dopaminergic neurons. Finally, we show that GABA-B receptor activation also produces inhibition of NALCN-mediated currents. Therefore, we identify NALCN as a core effector of inhibitory G protein-coupled receptors.

【 授权许可】

Unknown