Acetylcholine‐dependent upregulation of TASK‐1 channels in thalamic interneurons by a smooth muscle‐like signalling pathway. (3rd August 2017)

• Record Type: Journal Article
• Authors: Leist, Michael; Rinné, Susanne; Datunashvili, Maia; Aissaoui, Ania; Pape, Hans‐Christian; Decher, Niels; Meuth, Sven G.; Budde, Thomas
• Is Part Of: Journal of physiology. Volume 595:Number 17(2017)
• Page Start: 5875
• Page End: 5893
• Publication Date: 2017-08-03
• Subjects: interneuron -- K2P channels -- muscarinic modulation -- thalamus -- tyrosine kinase; Physiology -- Periodicals; 612.005
• DOI: 10.1113/JP274527
• Languages: English
• ISSNs: 0022-3751

Abstract

Abstract : Key points: The ascending brainstem transmitter acetylcholine depolarizes thalamocortical relay neurons while it induces hyperpolarization in local circuit inhibitory interneurons. Sustained K + currents are modulated in thalamic neurons to control their activity modes; for the interneurons the molecular nature of the underlying ion channels is as yet unknown. Activation of TASK‐1 K + channels results in hyperpolarization of interneurons and suppression of their action potential firing. The modulation cascade involves a non‐receptor tyrosine kinase, c‐Src. The present study identifies a novel pathway for the activation of TASK‐1 channels in CNS neurons that resembles cholinergic signalling and TASK‐1 current modulation during hypoxia in smooth muscle cells. Abstract: The dorsal part of the lateral geniculate nucleus (dLGN) is the main thalamic site for state‐dependent transmission of visual information. Non‐retinal inputs from the ascending arousal system and inhibition provided by γ‐ aminobutyric acid (GABA)ergic local circuit interneurons (INs) control neuronal activity within the dLGN. In particular, acetylcholine (ACh) depolarizes thalamocortical relay neurons by inhibiting two‐pore domain potassium (K2P ) channels. Conversely, ACh also hyperpolarizes INs via an as‐yet‐unknown mechanism. By using whole cell patch‐clamp recordings in brain slices and appropriate pharmacological tools we here report that stimulation of type 2 muscarinic ACh receptors induces IN hyperpolarization by recruiting the G‐protein βγ subunit (Gβγ), class‐1A phosphatidylinositol‐4, 5‐bisphosphate 3‐kinase, and cellular and sarcoma (c‐Src) tyrosine kinase, leading to activation of two‐pore domain weakly inwardly rectifying K + channel (TWIK)‐related acid‐sensitive K + (TASK)‐1 channels. The latter was confirmed by the use of TASK‐1‐deficient mice. Furthermore inhibition of phospholipase Cβ as well as an increase in the intracellular level of phosphatidylinositol‐3, 4, 5‐trisphosphate facilitated the muscarinic effect. Our results have uncovered a previously unknown role of c‐Src tyrosine kinase in regulating IN function in the brain and identified a novel mechanism by which TASK‐1 channels are activated in neurons. Key points: The ascending brainstem transmitter acetylcholine depolarizes thalamocortical relay neurons while it induces hyperpolarization in local circuit inhibitory interneurons. Sustained K + currents are modulated in thalamic neurons to control their activity modes; for the interneurons the molecular nature of the underlying ion channels is as yet unknown. Activation of TASK‐1 K + channels results in hyperpolarization of interneurons and suppression of their action potential firing. The modulation cascade involves a non‐receptor tyrosine kinase, c‐Src. The present study identifies a novel pathway for the activation of TASK‐1 channels in CNS neurons that resembles cholinergic signalling and TASK‐1 current modulation during hypoxia in smooth muscle cells.